WO2025210099A1

WO2025210099A1 - Method of treatment and selecting a subject

Info

Publication number: WO2025210099A1
Application number: PCT/EP2025/059020
Authority: WO
Inventors: Martin Jenkins; Fred REID; Hitesh Champaklal Pandya; Donna Kirsty Finch; Christopher Martin Kell
Original assignee: MedImmune Ltd
Current assignee: MedImmune Ltd
Priority date: 2024-04-04
Filing date: 2025-04-02
Publication date: 2025-10-09
Anticipated expiration: 2026-10-04

Abstract

The present disclosure relates to a method of treatment of a subject having chronic obstructive pulmonary disease, method of improving lung function in a subject having chronic obstructive pulmonary disease and a method of selecting a subject having chronic obstructive pulmonary disease for treatment.

Description

Method of treatment and selecting a subject

CROSS-REFERENCE TO RELATED PATENT APPLICATION

This specification claims the benefit of priority to U.S. Provisional Patent Application No. 63/574,724 (filed 4 April 2024). The entire text of the above-referenced patent application is incorporated by reference into this specification

TECHNICAL FIELD

The present disclosure relates to a method of treatment of a subject having chronic obstructive pulmonary disease, a method of improving lung function in a subject having chronic obstructive pulmonary disease and a method of selecting a subject having chronic obstructive pulmonary disease for treatment.

BACKGROUND

The following discussion is provided to aid the reader in understanding the disclosure and does not constitute any admission as to the contents or relevance of the prior art.

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the world and is projected to be the third leading cause of death worldwide by 2030 (Adeloye et al 2015). Chronic obstructive pulmonary disease is characterized by persistent respiratory symptoms and airflow limitation (post-BD FEVi/FVC < 0.70) that is due to airway and/or alveolar abnormalities, usually caused by significant exposure to noxious particles or gases, and influenced by host factors including abnormal lung development. Significant comorbidities may have an impact on morbidity and mortality (GOLD 2020). Chronic obstructive pulmonary disease is not fully reversible, usually progressive and associated with an enhanced chronic inflammatory response in the lung. Patients with active chronic bronchitis symptoms bear a greater burden of disease than those without and are characterized by more rapid loss of lung function, increased mortality and increased risk of exacerbation (Kim et al 2011; de Oca et al 2012; Corhay et al 2013; Kim and Criner 2013; Woodruff et al 2016; Lahousse et al 2017). Interleukin-33 expression is upregulated in the lungs of patients with COPD, is inversely correlated with lung function, and has a role in inflammatory and epithelial processes in COPD.

There is an increasing evidence base demonstrating that the overall symptomatic burden has a substantial detrimental impact on health related quality of life and also contributes to increased risk of exacerbations and a worse disease prognosis (Miravitlles and Ribera 2017).

Acute exacerbations of COPD are episodes of symptom worsening that have significant adverse consequences for patients (Wedzicha and Seemungal 2007). Greater frequency of exacerbations is associated with accelerated lung function decline, health-related quality of life impairment, and increased mortality (Donaldson et al 2002, Seemungal et al 1998, Soler-Cataluna et al 2005). Furthermore, as the incidence of COPD increases, exacerbations place a greater burden on health care systems, accounting for more than 10 million unscheduled attendances per year in the United States (Mannino and Braman 2007). The direct costs of COPD treatment in the United States are greater than $32 billion per year, with exacerbations estimated to account for 50% to 75% of these healthcare costs (Celli et al 2004, Guarascio et al 2013, Toy et al 2010). Exacerbations are also important outcome measures in COPD, with acute treatment targeting accelerated recovery from such exacerbations, whereas chronic treatment typically refers to long-term maintenance inhaled therapy designed to prevent and reduce their frequency and severity (Ritchie and Wedzicha 2020).

Despite adequate treatment with optimised maintenance inhaled therapy, approximately 30% to 40% of patients continue to have moderate or severe exacerbations (Miillerova et al 2017, Vestbo et al 2017). Even maximal triple therapy (LABA + LAMA + ICS) may still be insufficient (Rabe et al 2020).

As with many other diseases, COPD patients present with notable variability in disease severity, disease onset and speed of progression. Due to this vast disease variability, different patient subgroups may be best served by different and more tailored treatments. Hence, a substantial unmet medical need remains. The present disclosure is directed at solving one or more of the above-mentioned problems in the art. Accordingly, one or more aspects of the present disclosure and further instances thereof are defined hereinbelow.

Rabe et al Lancet Respir Med. 2021 Nov;9(l l): 1288-1298 discloses results of a randomised, doubleblind, phase 2a trial studying the safety and efficacy of itepekimab. Yousuf et al Lancet Respir Med 2022 May;10(5):469-477 disloses results from COPD-ST2OP: a phase 2a, placebo-controlled trial studying astegolimab effect in chronic obstructive pulmonary disease. WO2023/02593 discloses A Phase III, Multicentre, Randomised, Double-blind, Chronic-dosing, Parallel-group, Placebo-controlled Study to Evaluate the Efficacy and Safety of Two Dose Regimens of tozorakimab in Participants with Symptomatic Chronic Obstructive Pulmonary Disease (COPD) with a History of COPD Exacerbations (NCT05166889).

SUMMARY OF THE DISCLOSURE

In a first aspect, there is provided a method of treatment of a subject having COPD, the method comprising: administering to said subject an effective amount of an IL-33 signalling axis antagonist, wherein, prior to said administration the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl.

In a second aspect, there is provided a method of improving lung function in a subject having COPD, the method comprising: administering to said subject an effective amount of an IL-33 signalling axis antagonist, wherein, prior to said administration the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl. In a third aspect, there is provided a method of treatment of a subject having COPD, the method comprising: administering to said subject an effective amount of an IL-33 signalling axis antagonist, wherein, prior to said administration the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl, and wherein the subject is a current smoker.

In a fourth aspect, there is provided a method of improving lung function in a subject having COPD, the method comprising: administering to said subject an effective amount of an IL-33 signalling axis antagonist, wherein, prior to said administration the subject comprises a blood eosinophil count of from <250 to > 150 cells/pl, and wherein the subject is a current smoker.

In a fifth aspect, there is provided a method of increasing the time-to-first CompEx event in a subject having COPD, the method comprising: administering to said subject an effective amount of an IL-33 signalling axis antagonist, wherein the subject is a current smoker.

In a sixth aspect, there is provided a method of reducing the rate of CompEx events in a subject having COPD, the method comprising: administering to said subject an effective amount of an IL-33 signalling axis antagonist, wherein the subject is a current smoker.

In a further aspect, there is provided a method of increasing the time-to-first CompEx event in a subject having COPD, the method comprising: administering to said subject an effective amount of an IL-33 signalling axis antagonist, wherein the subject is a current smoker and wherein prior to said administration the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl.

In a further aspect, there is provided a method of reducing the rate of CompEx events in a subject having COPD, the method comprising: administering to said subject an effective amount of an IL-33 signalling axis antagonist, wherein the subject is a current smoker.

In a further aspect, there is provided a method of increasing pre-BD FEVi of a subject having COPD by at least 50 ml (such as at least 60 ml), the method comprising: administering to said subject an effective amount of an IL-33 signalling axis antagonist, wherein prior to said administration the subject comprises a blood eosinophil count of from <250 to > 150 cells/pl.

In a further aspect, there is provided a method of increasing pre-BD FEVi of a subject having COPD by at least 50 ml (such as at least 60 ml), the method comprising: administering to said subject an effective amount of an IL-33 signalling axis antagonist, wherein, prior to said administration the subject comprises a blood eosinophil count of from <250 to > 150 cells/pl, and wherein the subject is a current smoker.

In a further aspect, there is provided an IL-33 signalling axis antagonist for use in the treatment of COPD in a subject, wherein, prior to administration of the IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl. In a further aspect, there is provided an IL-33 signalling axis antagonist for use in improving lung function in a subject having COPD, wherein, prior to administration of the IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl. Optionally which aspect may be for use in the treatment of COPD by improving lung function.

In a further aspect, there is provided an IL-33 signalling axis antagonist for use in the treatment of COPD in a subject, wherein, prior to administration of the IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl, and wherein the subject is a current smoker.

In a further aspect, there is provided an IL-33 signalling axis antagonist for use in improving lung function in a subject having COPD, wherein, prior to administration of the IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl, and wherein the subject is a current smoker. Optionally which aspect may be for use in the treatment of COPD by improving lung function.

In a further aspect, there is provided an IL-33 signalling axis antagonist for use in increasing the time- to-first CompEx event in a subject having COPD, wherein the subject is a current smoker. Optionally which aspect may be for use in the treatment of COPD by increasing the time-to-first CompEx event.

In a further aspect, there is provided an IL-33 signalling axis antagonist for use in reducing the rate of CompEx events in a subject having COPD, wherein the subject is a current smoker. Optionally which aspect may be for use in the treatment of COPD by reducing the rate of CompEx events.

In a further aspect, there is provided an IL-33 signalling axis antagonist for use in increasing the time- to-first CompEx event in a subject having COPD, wherein the subject is a current smoker and wherein prior to administration of the IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl. Optionally which aspect may be for use in the treatment of COPD by increasing the time-to-first CompEx event.

In a further aspect, there is provided an IL-33 signalling axis antagonist for use in reducing the rate of CompEx events in a subject having COPD, wherein the subject is a current smoker and wherein prior to administration of the IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl. Optionally which aspect may be for use in the treatment of COPD by reducing the rate of CompEx events.

In a further aspect, there is provided an IL-33 signalling axis antagonist for use in increasing pre-BD FEVi of a subject having COPD by at least 50 ml (such as at least 60 ml), wherein, prior to administration of the IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from <250 to > 150 cells/pl. Optionally which aspect may be for use in the treatment of COPD by increasing pre-BD FEVi. In a further aspect, there is provided an IL-33 signalling axis antagonist for use in increasing pre-BD FEVi of a subject having COPD by at least 50 ml (such as at least 60 ml), wherein, prior to administration of the IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from <250 to > 150 cells/pl, and wherein the subject is a current smoker. Optionally which aspect may be for use in the treatment of COPD by increasing pre-BD FEVi.

In a seventh aspect, there is provided a method of selecting a subject having COPD for treatment with an effective amount of IL-33 signalling axis antagonist, the method comprising: measuring the blood eosinophil count of the subject; selecting said subject for said treatment if the blood eosinophil count of the subject is from < 250 to > 150 cells/pl; optionally administering an effective amount of IL-33 signalling axis antagonist to the subject.

In an eighth aspect, there is provided a method of selecting a subject having COPD for treatment with an effective amount of IL-33 signalling axis antagonist, the method comprising: measuring the blood eosinophil count of the subject; selecting said subject for said treatment if the blood eosinophil count of the subject is from < 250 to > 150 cells/pl and said subject is a current smoker; optionally administering an effective amount of IL-33 signalling axis antagonist to the subject.

In a ninth aspect, there is provided the use of an IL-33 signalling axis antagonist in the manufacture of a medicament for the treatment of COPD in a subject, wherein, prior to administration of the IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl.

In a tenth aspect, there is provided the use of an IL-33 signalling axis antagonist in the manufacture of a medicament for improving lung function in a subject having COPD, wherein, prior to administration of the IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl. Optionally which aspect may be for the treatment of COPD by improving lung function.

In an eleventh aspect, there is provided the use of an IL-33 signalling axis antagonist in the manufacture of a medicament for the treatment of COPD in a subject, wherein, prior to administration of the IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl, and wherein the subject is a current smoker.

In a twelfth aspect, there is provided the use of an IL-33 signalling axis antagonist in the manufacture of a medicament for improving lung function in a subject having COPD, wherein, prior to administration of the IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl, and wherein the subject is a current smoker. Optionally which aspect may be for the treatment of COPD by improving lung function. In a thirteenth aspect, there is provided the use of an IL-33 signalling axis antagonist in the manufacture of a medicament for increasing the time-to-first CompEx event in a subject having COPD, wherein the subject is a current smoker. Optionally which aspect may be for the treatment of COPD by increasing the time-to-first CompEx event.

In a fourteenth aspect, there is provided the use of an IL-33 signalling axis antagonist in the manufacture of a medicament for reducing the rate of CompEx events in a subject having COPD, wherein the subject is a current smoker. Optionally which aspect may be the treatment of COPD by reducing the rate of CompEx events.

In a fifteenth aspect, there is provided the use of an IL-33 signalling axis antagonist in the manufacture of a medicament for increasing the time-to-first CompEx event in a subject having COPD, wherein the subject is a current smoker and wherein prior to administration of the IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl. Optionally which aspect may be for the treatment of COPD by increasing the time-to-first CompEx event.

In a sixteenth aspect, there is provided the use of an IL-33 signalling axis antagonist in the manufacture of a medicament for reducing the rate of CompEx events in a subject having COPD, wherein the subject is a current smoker and wherein prior to administration of the IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl. Optionally which aspect may be for the treatment of COPD by reducing the rate of CompEx events.

In a seventeenth aspect there is provided the use of an IL-33 signalling axis antagonist in the manufacture of a medicament for increasing pre-BD FEVi of a subject having COPD by at least 50 ml (such as at least 60 ml), wherein, prior to administration of the IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from <250 to > 150 cells/pl. Optionally which aspect may be for the treatment of COPD by increasing pre-BD FEVi.

In an eighteenth aspect there is provided the use of an IL-33 signalling axis antagonist in the manufacture of a medicament for increasing pre-BD FEVi of a subject having COPD by at least 50 ml (such as at least 60 ml), wherein, prior to administration of the IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from <250 to > 150 cells/pl, and wherein the subject is a current smoker. Optionally which aspect may be for the treatment of COPD by increasing pre-BD FEVi.

In further alternative aspects of the disclosure, there is provided a method of treatment of a subject having COPD, the method comprising: administering to said subject an effective amount of an IL-33 signalling axis antagonist, wherein the subject is a current smoker. In further alternative aspects of the disclosure, there is provided a method of improving lung function in a subject having COPD, the method comprising: administering to said subject an effective amount of an IL-33 signalling axis antagonist, wherein the subject is a current smoker.

In further alternative aspects of the disclosure, there is provided a method of increasing pre-BD FEVi of a subject having COPD by at least 50 mL (such as at least 60 ml), the method comprising: administering to said subject an effective amount of an IL-33 signalling axis antagonist, wherein the subject is a current smoker.

In further alternative aspects of the disclosure, there is provided an IL-33 signalling axis antagonist for use in the treatment of COPD in a subject, wherein the subject is a current smoker.

In further alternative aspects of the disclosure, there is provided an IL-33 signalling axis antagonist for use in improving lung function in a subject having COPD, wherein the subject is a current smoker. Optionally which aspect may be for use in the treatment of COPD by improving lung function.

In further alternative aspects of the disclosure, there is provided an IL-33 signalling axis antagonist for use in increasing pre-BD FEVi of a subject having COPD by at least 50 mL (such as at least 60 ml), wherein the subject is a current smoker. Optionally which aspect may be for use in the treatment of COPD by increasing pre-BD FEVi.

In further alternative aspects of the disclosure, there is provided the use of an IL-33 signalling axis antagonist in the manufacture of a medicament for the treatment of COPD in a subject, wherein the subject is a current smoker.

In further alternative aspects of the disclosure, there is provided the use of an IL-33 signalling axis antagonist in the manufacture of a medicament for improving lung function in a subject having COPD, wherein the subject is a current smoker. Optionally which aspect may be for the treatment of COPD by improving lung function.

In further alternative aspects of the disclosure, there is provided the use of an IL-33 signalling axis antagonist in the manufacture of a medicament for increasing pre-BD FEVi of a subject having COPD by at least 50 ml (such as at least 60 ml), wherein the subject is a current smoker. Optionally which aspect may be for the treatment of COPD by increasing pre-BD FEVi.

FRONTIER-4 (NCT04631016) is a phase II, randomized, double-blind, placebo-controlled study to assess tozorakimab (MEDI3506) in participants with COPD and Chronic Bronchitis. This trial shows that particular subsets of patients with COPD exhibit enhanced therapeutic responses when administered an anti -IL-33 antibody such as tozorakimab. The present disclosure aims to capture the treatment of said subsets of patients which may benefit more from treatment with such IL-33 signalling axis antagonists as tozorakimab.

Further features and instances of the above defined aspects are described hereinbelow in headed sections. Each section is combinable with any of the above mentioned aspects in any compatible combination.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 shows the Change From Baseline Through Week 36 in Pre-BD FEVi (L) (Clinic), (ITT Population) (MEDI3506 600mg vs placebo).

Figure 2 shows the Change in Pre-BD FEVi (L) Measured in the Clinic at Week 12, in subgroups with higher BCSS or SGRQ scores, in former and current smokers, lower emphysema or >2 COPD exacerbations in 12 months prior to enrolment.

Figure 3 shows the Change in Post-BD FEVi Measured in Clinic (MEDI3506 600mg vs placebo).

Figure 4 Change From Baseline Through Week 36 in pre-BD FVC (L) (Clinic), (ITT population) (MEDI3506 600mg vs placebo).

Figure 5 shows the Time to First COPDCompEx Event (Days), Kaplan-Meier plot (ITT Population) (MEDI3506 600mg vs placebo).

Figure 6A shows the time-to-first CompEx event in former smokers compared to former smokers treated with placebo.

Figure 6B shows the time-to-first CompEx event in current smokers compared to current smokers treated with placebo.

DETAILED DESCRIPTION

Definitions

The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain instances, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain instances, the term “about” or “approximately” means within 30%, 25%, 20%, 15%, 1 0%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. Whenever the term “about” or “approximately” precedes the first numerical value in a series of two or more numerical values, it is understood that the term “about” or “approximately” applies to each one of the numerical values in that series.

In certain instances, the symbol ‘<’ means Tess than’ and ‘>’ means ‘more than’ the designated number following the symbol, wherein the designated number following the symbol is not included in said range. On the contrary, the symbol ‘<’ means ‘less than or equal to’ and the symbol ‘>’ means ‘more than or equal to’ than’ the designated number following the symbol, wherein the designated number following the symbol is included in the range.

It is to be noted that the term "a" or "an" entity refers to one or more of that entity; for example, “an anti -IL-33 antibody” is understood to represent one or more anti -IL-33 antibodies. As such, the terms “a” (or “an”), “one or more,” and “at least one” can be used interchangeably herein.

‘IL-33’ protein as employed herein refers to interleukin 33, in particular a mammalian interleukin 33 protein, for example human protein deposited with UniProt number 095760. However, it clear that this entity is not a single species but instead exists as reduced and oxidized forms. Given the rapid oxidation of the reduced form in vivo, for example in the period 5 minutes to 40 minutes, and in vitro, prior art references to IL-33 may actually be references to the oxidized form. Furthermore, commercial assays may not effectively discriminate between the reduced and oxidized forms. The terms "IL-33" and "IL- 33 polypeptide" are used interchangeably. In certain instances, IL-33 is full length. In another instance, IL-33 is mature, truncated IL-33 (amino acids 112-270). Recent studies suggest full length IL-33 is active (Cayrol and Girard, Proc Natl Acad Sci USA 106(22): 9021-6 (2009); Hayakawa et al., Biochem Biophys Res Commun. 387(l):218-22 (2009); Talabot-Ayer et al, J Biol Chem. 284(29): 19420-6 (2009)). However, N-terminally processed or truncated IL-33 including but not limited to aa 72-270, 79-270, 95-270, 99-270, 107-270, 109-270, 111-270, 112-270 may have enhanced activity (Lefrancais 2012, 2014). In another instance, IL-33 may include a full length IL-33, a fragment thereof, or an IL- 33 mutant or variant polypeptide, wherein the fragment of IL-33 or IL-33 variant polypeptide retains some or all functional properties of active IL-33.

It should be understood that references to “WT IL-33" or “IL-33” may refer to either the reduced or oxidised forms, or both, unless it is clear from the context within which it is used that one of the forms is meant.

As used herein, the terms “treat” or “treatment” refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

By “subject” or “individual” or “animal” or “patient” or “mammal,” is meant any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired, except where the subject is defined as a ‘healthy subject’. Mammalian subjects include humans; domestic animals; farm animals; such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows, and so on.

“IL-33 signalling axis antagonist” as employed herein refers to any agent which attenuates IL-33 activity, for example, reduced IL-33 activity, oxidised IL-33 activity or the activity of both. Suitably, the IL-33 signalling axis antagonist may be selected from: an antibody, an antigen -binding fragment thereof, an aptamer, at least one heavy or light chain CDR of a reference antibody molecule, and at least six CDRs from one or more reference antibody molecules. Suitably, the IL-33 signalling axis antagonist is an antibody or binding fragment thereof. Suitably, the IL-33 signalling axis antagonist is an anti -IL-33 antibody or binding fragment thereof. Suitably, the anti -IL-33 antibody or binding fragment thereof specifically binds to IL-33.

“Antibody” is used in the broadest sense and encompasses various immunoglobulin molecules and antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity, In particular a full-length antibody or a molecule comprising a full-length antibody, for example a DVD-Ig molecule and the like.

A “binding fragment thereof’ is interchangeable with “antigen binding fragment thereof’ and refers to an epitope/antigen binding fragment of an antibody fragment, for example comprising a binding region, in particular comprising 6 CDRs, such as 3 CDRs in heavy variable region and 3 CDRs in light variable region.

The term “effective amount” or “therapeutically effective amount” of an agent, e.g., a IL-33 signalling axis antagonist or a pharmaceutical formulation comprising an IL-33 signalling axis antagonist refers to an amount sufficient to achieve benefit or a therapeutic effect, such as to ameliorate symptoms of a disease or condition e.g. an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.

The terms "complementarity determining regions" and “CDRs” as used herein refer to the amino acid residues of an antibody or antigen-binding fragment that are responsible for antigen binding.

The terms “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprise a protein’s or peptide’s sequence. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. “Polypeptides” include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. A polypeptide includes a natural peptide, a recombinant peptide, or a combination thereof.

The term "nucleic acid" or "polynucleotide" refers to deoxyribonucleic acids (DNA) or ribonucleic acids (RNA) and polymers thereof in either single- or double -stranded form. Unless specifically limited, the term encompasses nucleic acids containing known analogues of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed- base and/or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al, J. Biol. Chem. 260:2605-2608 (1985); and Rossohm et al, Mol. Cell. Probes 8:91-98 (1994)).

The term “pack-years” refers to the average number of cigarettes per day x number of years / 20.

The term “COPD” refers to chronic obstructive pulmonary disease.

The term “COPDCompEx” refers to a composite endpoint for exacerbations in COPD. The COPDCompEx combines exacerbations with events defined from participant e-Diaries and Peak Expiratory Flow (PEF). Note the COPDCompEx definition typically includes dropout due to lack of efficacy as a CompEx event. However, in studies where Tack of efficacy’ is not listed as a reason for discontinuation, the drop out criterion for COPD CompEx may not be included.

A participant will be considered to have a CompEx event during the planned intervention period if the participant has one or more of the following:

• COPDCompEx defined exacerbation, those collected in eCRF with at least one of the following criteria met: o Associated Hospitalizations = Yes; o Systemic Corticosteroids (injected and/or oral) = Yes; o Antibiotics = Yes; o Any emergency room visit due to COPD exacerbation? = Yes.

• A diary event - An objective deterioration, which is defined as either the threshold criterion or the slope criterion (or both), being met for >2 consecutive days.

For this purpose, “2 consecutive days” means strictly the same 2 consecutive days when assessing multiple requirements within those days. For the eDiary data (which is captured twice during the day), one day will be defined by the evening/moming pairing as the other eDiary endpoints in this trial. Diary data recorded in the evening of day n and in the morning of day n+1 will belong to study day n.

The fulfilment of objective deterioration criteria will be calculated for each (single) diary variable for thresholds and slopes:

Threshold criterion - the threshold assessment in each 2-day rolling period: a. > 12% decrease from baseline in morning PEF. b. > 1.75 doses increase from baseline in daily total rescue medication (one day is defined as evening/moming pairing. The number of doses of rescue medication is defined as the number of puffs of inhaler recorded in the evening and morning, respectively.) If either the evening or morning result is missing then the single nonmissing result will be used. c. > 0.75 increase from baseline or having maximal symptom score 4 in at least one of the symptom scores: breathlessness, cough, sputum. To be specific: i. > 0.75 increase from baseline or having maximal symptom score 4 in breathlessness daily score; ii. > 0.75 increase from baseline or having maximal symptom score 4 in cough daily score; or iii. > 0.75 increase from baseline or having maximal symptom score 4 in sputum daily score.

The threshold criterion is met if [(a) or (b)] and at least one of (c) are met on 2 consecutive days.

Slope criterion - the regression slope assessment in each preceding 5 -day rolling period: d. Morning PEF slopes < -3%/day. e. Daily total rescue medication slope > 0.4 doses/day f. Slope > 0.2/day in all of symptom scores breathlessness, cough, sputum.

The slope criterion is met if [(d), (e) and (f)] are all met, and at least one of [(a), (b) or (c)] is met.

In all of the above cases, the regression slope is the point estimate of the slope obtained from a linear regression of the absolute values of each of the variables separately against day number, with no other variables included in the regression model.

The phrase “prior to administration” refers to a time within one month of the commencement of the treatment. Optionally prior to administration may refer to any time within one month of the commencement of the treatment, for example 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks or 4 weeks before commencement of the treatment.

The term “emphysema” refers to damage to the air sacs in the lungs. The term “chronic bronchitis” refers to long term inflammation of the airways, and may be defined as the presence of cough and sputum on most days for > 3 months/year in at least the 2 years prior.

The term “BCSS score” refers to the score from the breathlessness, cough and sputum scale (BCSS). The BCSS is a 3-item PRO (Leidy et al Chest. 2003;124(6):2182-91, Leidy et al Respir Med. 2003;97 Suppl AS59-70) that assesses the severity of breathlessness, cough, and sputum on a scale of 0 (no symptoms) to 4 (severe symptoms). Item scores are summed to yield a total score, with higher scores indicating more severe symptoms.

The term “SGRQ score” is the score from the St. George’s Respiratory Questionnaire (SGRQ).. The SGRQ is a 50-item PRO instrument developed to measure the health status of patients with airway obstruction diseases (Jones PW, Quirk FH and Baveystock CM. The St George's Respiratory Questionnaire. Respir Med 1991 ;85 Suppl B:25-31.). The questionnaire is divided into 2 parts: part 1 consists of 8 items pertaining to the severity of respiratory symptoms in the preceding 4 weeks; part 2 consists of 42 items related to the daily activity and psychosocial impacts of the individual’s respiratory condition. The SGRQ yields a total score and 3 domain scores (symptoms, activity, and impacts). The total score indicates the impact of disease on overall health status. This total score is expressed as a percentage of overall impairment, in which 100 represents the worst possible health status and 0 indicates the best possible health status. Likewise, the domain scores range from 0 to 100, with higher scores indicative of greater impairment. Specific details on the scoring algorithms are provided by the developer in a user manual (Jones PW and Forde Y. St George’s respiratory questionnaire manual. 2009. Version 2.3). SGRQ is a qualified biomarker and the responder definition is generally a 4 point improvement from baseline. Accordingly, in some instances, the minimum clinical important difference for SGRQ is 4.

The term “pre-BD FEVi” , “pre-BD FEVi”or “pre-bronchodilator (BD) FEVi” refers to prebronchodilator forced expiratory volume 1. This is a measurement of forced expiratory volume of a subj ect in 1 second before administration of bronchodilator. pre-BD FEV i is an important measurement of lung function.

The term “post-BD-FEVi” or “post-bronchodilator (BD)-FEVi” refers to post-bronchodilator Forced expiratory volume 1. This is a measurement of forced expiratory volume of a subject in 1 second after administration of bronchodilator. post-BD FEVi is an important measurement of lung function.

The term “pre-BD-FVC” or “pre-bronchodilator (BD) forced vital capacity (FVC)” refers to bronchodilator Forced vital capacity. This is the total amount of air exhaled by a subject during a forced expiratory volume test or FVC test before administration of bronchodilator. pre-BD FVC is an important measurement of lung function. The term “post-BD-FVC” or “post-bronchodilator (BD)-FVC” refers to post-bronchodilator forced vital capacity. This is the total amount of air exhaled by a subject during a forced expiratory volume test or FVC test after administration of bronchodilator. post-BD FVC is an important measurement of lung function.

The term “bronchodilator” is a substance which dilates the bronchi and bronchioles, decreasing resistance in the respiratory airways and increasing airflow to the lungs. Suitable bronchodilators include short-acting 02 adrenergic receptor agonists, such as salbutamol.

The term “minute volume” indicates the total amount of air exhaled per minute of a subject.

The term “vital capacity” indicates the total volume of air that can be exhaled by a subject after inhaling as much as possible.

The term “functional residual capacity” indicates the amount of air left in the lungs of a subject after exhaling normally.

The term “residual volume” indicates the amount of air left in the lungs of a subject after exhaling as much as possible.

The term “total lung volume” indicates the total volume of the lungs of a subject when filled with as much air as possible.

The term “forced expiratory flow” indicates the average rate of flow of air expired by a subject during the middle half of the FVC test.

The term “peak expiratory flow rate” indicates the fastest rate that a subject can force air out of the lungs.

The term “forced expiratory volume (FEV)” is amount of air expired by a subject during the first, second, and third seconds of the FVC test. The term FEVi as explained above is the amount of air expired by a subject during the first second of the FVC test.

The term “forced vital capacity” (FVC) or the forced vital capacity test is a measurement of the total amount of air exhaled forcefully and quickly by a subject after inhaling as much as possible.

The term “placebo group” refers to a group of control subjects having the same characteristics as the subject to be treated, who have not received the IL-33 signalling axis antagonist but who have received a placebo. Suitably the placebo is a pharmacologically inert preparation or composition. Suitably the placebo may contain the same ingredients as a pharmaceutical composition containing the IL-33 signalling axis antagonist with the exception that it does not contain the active IL-33 signalling axis antagonist. Subject

The methods and medical uses are practiced in respect of a subject. Suitably the subject may be a human. Suitably the subject may be undergoing medical care. Suitably the subject may be an individual requesting medical care. Suitably the subject is male or female. Suitably the subject is an adult or a child. Suitably the term ‘subject’ is used herein interchangeably with the term ‘patient’.

Suitably the subject has COPD, is suspected of having COPD, or has symptoms consistent with COPD. Suitably the subject having COPD may mean the subject has a diagnosis of COPD. The subject may have a documented history of COPD, suitably for at least 1 year prior to undergoing the treatments disclosed herein.

In some instances, the subject is a current smoker. In some instances, the subject is a former smoker.

In some instances, the subject is a current smoker or former smoker with a tobacco history of more than or equal to (=> or >) 10 pack-years. Pack -years are calculated as average number of cigarettes per day x number of years / 20. For example, 1 pack -year = 20 cigarettes smoked per day for 1 year or 10 cigarettes per day for 2 years. In some instances, the subject may have a tobacco history of > 5 pack- years, > 6 pack-years, > 7 pack-years, > 8 pack-years, > 9 pack-years, or > 10 pack-years. Suitably the subject may have a tobacco history of > 15 pack-years, > 20 pack-years, > 25 pack-years, > 30 pack- years, > 15 pack-years, > 15 pack-years. In some instances, the subject is a former smoker with a tobacco history of > 10 pack-years. In some instances, the subject is a current smoker. In some instances, the subject is a current smoker with a tobacco history of > 10 pack-years.

The results demonstrate that tozorakimab (MEDI3506) had similar numerical improvements in clinic pre-BD FEVi in both former and current smokers (see Figure 1 and 2), as well as improvements in the time to first CompEX event (Figures 6A and 6B) in both former and current smokers. Conversely, in a phase 2a trial to assess the safety and efficacy of itepekimab in patients with moderate-to-severe COPD, current smokers treated with itepekimab showed no treatment benefit versus placebo for exacerbations or FEV i on a stable regimen of triple-inhaled or double-inhaled background maintenance therapy (Rabe et al (2021) Lancet Respi Med\ 9:11; 1288-1298). Itepekimab is an anti-IL-33 monoclonal antibody.

In some instances, the subject is a never smoker.

Suitably prior to administration of the effective amount of an IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of greater than or equal to > 150 cells/pl. Suitably prior to administration of the effective amount of an IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of less than < 300 cells/pl. Suitably prior to administration of the effective amount of an IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from < 300 to > 150 cells/pl. Suitably prior to administration of the effective amount of an IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from < 290 to > 150 cells/pl. Suitably prior to administration of the effective amount of an IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from < 280 to > 150 cells/pl. Suitably prior to administration of the effective amount of an IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from

< 270 to > 150 cells/pl. Suitably prior to administration of the effective amount of an IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from < 260 to > 150 cells/pl.

Suitably prior to administration of the effective amount of an IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from < 230 to > 150 cells/pl. Suitably prior to administration of the effective amount of an IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from < 220 to > 150 cells/pl. Suitably prior to administration of the effective amount of an IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from

< 210 to > 150 cells/pl. Suitably prior to administration of the effective amount of an IL-33 signalling axis antagonist the subject comprises a blood eosinophil count of from < 200 to > 150 cells/pl.

In some instances, prior to said administration the subject comprises a blood eosinophil count of < 300,

< 290, < 280, < 270, < 260, < 250, < 240, < 230, < 220, < 210, < 200 cells/pl.

In some instances, prior to said administration the subject comprises a blood eosinophil count of < 250 cells/pl, (suitably which does not include 250 cells/pl). In some particularly instances, prior to said administration the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl, (suitably which does not include 250 cells/pl).

In some instances, prior to said administration the subject comprises a blood eosinophil count of < 240 cells/pl, (suitably which does not include 250 cells/pl). In some instances, prior to said administration the subject comprises a blood eosinophil count of from < 240 to > 150 cells/pl, (suitably which does not include 240 cells/pl).

The results demonstrate that tozorakimab (MEDI3506) had sustained numerical improvement in clinic and at-home pre-BD FEVi throughout a treatment period up to 12 weeks in subjects with blood eosinophil counts > 300 cells/pl, but also for those subjects with low blood eosinophil counts of less than 300 cells/pl, down to > 150 cells/pl (see Figures 1-2 and 7). Improvement in pre-BD FEVi throughout a treatment period up to 28 weeks was especially shown in the subgroup of subjects having a blood eosinophil count of between < 250 to > 150 cells/pl, not including 250 cells/pl (see Table 10 results). No other IL-33 signalling axis antagonists have been shown to have such an effect on lung function as evidenced by pre-BD FEVi, in a subgroup with low eosinophil counts, particularly between

< 250 to > 150 cells/pl. Furthermore, the results demonstrate that tozorakimab (MEDI3506) reduced the rate of CompEx events in all subjects, but especially in the subgroup of subjects having a blood eosinophil count of > 150 cells/pl (see Table 9). In some instances, the subject is a current or former smoker. Suitably the subject is a former smoker. In some instances, the subject is a current smoker. Suitably the subject is a non-smoker.

The subject may be a current or former smoker and comprise a blood eosinophil count of from < 300 to > 150 cells/pl prior to administration of the effective amount of an IL-33 signalling axis antagonist. The subject may be a current or former smoker and comprise a blood eosinophil count of from < 290 to > 150 cells/pl prior to administration of the effective amount of an IL-33 signalling axis antagonist. The subject may be a current or former smoker and comprise a blood eosinophil count of from < 280 to > 150 cells/pl prior to administration of the effective amount of an IL-33 signalling axis antagonist. The subject may be a current or former smoker and comprise a blood eosinophil count of from < 270 to > 150 cells/pl prior to administration of the effective amount of an IL-33 signalling axis antagonist. The subject may be a current or former smoker and comprise a blood eosinophil count of from < 260 to > 150 cells/pl prior to administration of the effective amount of an IL-33 signalling axis antagonist.

In some instances, the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl and is a current or former smoker. In some instances, the subject comprises a blood eosinophil count of from < 240 to > 150 cells/pl and is a current or former smoker.

The subject may be a current or former smoker and comprise a blood eosinophil count of from < 230 to > 150 cells/pl prior to administration of the effective amount of an IL-33 signalling axis antagonist. The subject may be a current or former smoker and comprise a blood eosinophil count of from < 220 to > 150 cells/pl prior to administration of the effective amount of an IL-33 signalling axis antagonist. The subject may be a current or former smoker and comprise a blood eosinophil count of from < 210 to > 150 cells/pl prior to administration of the effective amount of an IL-33 signalling axis antagonist. The subject may be a current or former smoker and comprise a blood eosinophil count of from < 200 to > 150 cells/pl prior to administration of the effective amount of an IL-33 signalling axis antagonist.

In some instances, prior to said administration the subject comprises a blood eosinophil count of < 300, < 290, < 280, < 270, < 260, < 250, < 240, < 230, < 220, < 210, < 200 cells/pl and is a current or former smoker.

In some instances, prior to said administration the subject comprises a blood eosinophil count of < 250 cells/pl, (suitably which does not include 250 cells/pl) and is a current or former smoker. In some instances, prior to said administration the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl, (suitably which does not include 250 cells/pl) and is a current or former smoker.

In some instances, prior to said administration the subject comprises a blood eosinophil count of < 240 cells/pl, (suitably which does not include 250 cells/pl) and is a current or former smoker. In some instances, prior to said administration the subject comprises a blood eosinophil count of from < 240 to > 150 cells/pl, (suitably which does not include 240 cells/pl) and is a current or former smoker. In some instances, the subject comprises a blood eosinophil count of from < 300 to > 150 cells/pl, and is a current smoker.

The subject may be a current smoker and comprise a blood eosinophil count of from < 290 to > 150 cells/pl prior to administration of the effective amount of an IL-33 signalling axis antagonist. The subject may be a current smoker and comprise a blood eosinophil count of from < 280 to > 150 cells/pl prior to administration of the effective amount of an IL-33 signalling axis antagonist. The subject may be a current smoker and comprise a blood eosinophil count of from < 270 to > 150 cells/pl prior to administration of the effective amount of an IL-33 signalling axis antagonist. The subject may be a current smoker and comprise a blood eosinophil count of from < 260 to > 150 cells/pl prior to administration of the effective amount of an IL-33 signalling axis antagonist.

In some instances, the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl and is a current smoker. In some instances, the subject comprises a blood eosinophil count of from < 240 to > 150 cells/pl and is a current smoker.

The subject may be a current smoker and comprise a blood eosinophil count of from < 230 to > 150 cells/pl prior to administration of the effective amount of an IL-33 signalling axis antagonist. The subject may be a current smoker and comprise a blood eosinophil count of from < 220 to > 150 cells/pl prior to administration of the effective amount of an IL-33 signalling axis antagonist. The subject may be a current smoker and comprise a blood eosinophil count of from < 210 to > 150 cells/pl prior to administration of the effective amount of an IL-33 signalling axis antagonist. The subject may be a current smoker and comprise a blood eosinophil count of from < 200 to > 150 cells/pl prior to administration of the effective amount of an IL-33 signalling axis antagonist.

In some instances, prior to said administration the subject comprises a blood eosinophil count of < 300, < 290, < 280, < 270, < 260, < 250, < 240, < 230, < 220, < 210, < 200 cells/pl and is a current smoker.

In some instances, prior to said administration the subject comprises a blood eosinophil count of < 250 cells/pl, (suitably which does not include 250 cells/pl) and is a current smoker. In some instances, prior to said administration the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl, (suitably which does not include 250 cells/pl) and is a current smoker.

In some instances, prior to said administration the subject comprises a blood eosinophil count of < 240 cells/pl, (suitably which does not include 240 cells/pl) and is a current smoker. In some instances, prior to said administration the subject comprises a blood eosinophil count of from < 240 to > 150 cells/pl, (suitably which does not include 240 cells/pl) and is a current smoker.

In some instances, the methods of treatment described herein may comprise a further step of selecting a subject having a specific blood eosinophil count. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 300 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist.

The subject may be selected from a group of subjects comprising a blood eosinophil count of from< 290 to > 150 cells/pl prior to said administration. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 280 to > 150 cells/pl prior to said administration. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 280 to > 150 cells/pl prior to said administration. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 260 to > 150 cells/pl prior to said administration.

In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of from < 250 to > 150 cells/pl prior to said administration. In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of from < 240 to > 150 cells/pl prior to said administration.

The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 230 to > 150 cells/pl prior to said administration. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 220 to > 150 cells/pl prior to said administration. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 210 to > 150 cells/pl prior to said administration. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 200 to > 150 cells/pl prior to said administration.

In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of < 300, < 290, < 280, < 270, < 260, < 250, < 240, < 230, < 220, < 210, < 200 cells/pl prior to said administration.

In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of < 250 cells/pl, (suitably which does not include 250 cells/pl) prior to said administration. In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of from

< 250 to > 150 cells/pl, (suitably which does not include 250 cells/pl) prior to said administration.

In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of < 240 cells/pl, (suitably which does not include 250 cells/pl) prior to said administration. In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of from

< 240 to > 150 cells/pl, (suitably which does not include 240 cells/pl) prior to said administration.

The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 300 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 290 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 280 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 270 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 260 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers.

In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of from < 250 to > 150 cells/pl prior to said administration who are current or former smokers. In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of from < 240 to > 150 cells/pl prior to said administration who are current or former smokers.

The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 230 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 220 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 210 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 200 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers.

In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of < 300, < 290, < 280, < 270, < 260, < 250, < 240, < 230, < 220, < 210, < 200 cells/pl of the IL-33 signalling axis antagonist who are current or former smokers.

In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of < 250 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist who are current or former smokers. In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of from < 250 to > 150 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist who are current or former smokers.

In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of < 240 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist who are current or former smokers. In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of from < 240 to > 150 cells/pl, (suitably which does not include 240 cells/pl) of the IL-33 signalling axis antagonist who are current or former smokers.

The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 300 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 290 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 280 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 270 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 260 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers.

In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of from < 250 to > 150 cells/pl prior to said administration who are current smokers. In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of from < 240 to > 150 cells/pl prior to said administration who are current smokers.

The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 230 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 220 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 210 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers. The subject may be selected from a group of subjects comprising a blood eosinophil count of from < 200 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers.

In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of < 300, < 290, < 280, < 270, < 260, < 250, < 240, < 230, < 220, < 210, < 200 cells/pl of the IL-33 signalling axis antagonist who are current smokers.

In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of < 250 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist who are current smokers. In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of from < 250 to > 150 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist who are current smokers.

In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of < 240 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist who are current smokers. In some instances, the subject is selected from a group of subjects comprising a blood eosinophil count of from < 240 to > 150 cells/pl, (suitably which does not include 240 cells/pl) of the IL-33 signalling axis antagonist who are current smokers. In some instances, the subject further has chronic bronchitis. Subjects with active chronic bronchitis symptoms bear a greater burden of disease than those without and are characterized by more rapid loss of lung function, increased mortality and increased risk of exacerbation. Suitably the subject may have cough and sputum on most days for > 3 months/year in at least the 2 years prior to receiving the treatment disclosed herein.

In some instances, the subject comprises a BCSS score of around 7 or higher, 7.1 or higher, 7.2 or higher, 7.3 or higher, 7.4 or higher, 7.429 or higher. The BCSS scale is out of 12 with higher scores indicating more severe disease. Suitably, the subject has a BCSS score of > 6. Suitably, the subject has a BCSS score of > 7. Suitably, the subject has a BCSS score of > 7.1. Suitably, the subject has a BCSS score of> 7.2. Suitably, the subject has a BCSS score of> 7.3. Suitably, the subject has a BCSS score around 7.4. Suitably, the BCSS score is measured before, suitably immediately prior to, administration of the effective amount of an IL-33 signalling axis antagonist. Suitably the BCSS score may be given in sputum and/or cough. Suitably this may be assessed over a period of days as an average score, suitably over a period of 2 days, 5 days, 7 days, 10 days, or 14 days, suitably before administration of the effective amount of an IL-33 signalling axis antagonist. Suitably the subject may have an average BCSS score of > 2 in cough and > 2 in sputum domains assessed over 14 days.

Suitably the term “BCSS score” refers to the score from the breathlessness, cough and sputum scale (BCSS). The BCSS is a 3-item PRO (Leidy et al Chest. 2003;124(6):2182-91, Leidy et al Respir Med. 2003 ;97 Suppl AS59-70) that assesses the severity of breathlessness, cough, and sputum on a scale of 0 (no symptoms) to 4 (severe symptoms). Item scores are summed to yield a total score, with higher scores indicating more severe symptoms.

In some instances, the subject comprises a SGRQ score of around 58 or higher, 58.1 or higher, 58.2 or higher, 58.239 or higher. The SGRQ scale is out of 100 with higher scores indicating more severe disease. Suitably, the subject has a SGRQ score of > 50. Suitably, the subject has a SGRQ score of > 52. Suitably, the subject has a SGRQ score of > 54. Suitably, the subject has a SGRQ score of > 56. Suitably, the subject has a SGRQ score of > 58. Suitably, the SGRQ score is measured before, suitably immediately prior to, administration of the effective amount of an IL-33 signalling axis antagonist.

Sutiably the term “SGRQ score” is the score from the St. George’s Respiratory Questionnaire (SGRQ).. The SGRQ is a 50-item PRO instrument developed to measure the health status of patients with airway obstruction diseases (Jones PW, Quirk FH and Baveystock CM. The St George's Respiratory Questionnaire. Respir Med 1991 ;85 Suppl B:25-3L). The questionnaire is divided into 2 parts: part 1 consists of 8 items pertaining to the severity of respiratory symptoms in the preceding 4 weeks; part 2 consists of 42 items related to the daily activity and psychosocial impacts of the individual’s respiratory condition. The SGRQ yields a total score and 3 domain scores (symptoms, activity, and impacts). The total score indicates the impact of disease on overall health status. This total score is expressed as a percentage of overall impairment, in which 100 represents the worst possible health status and 0 indicates the best possible health status. Likewise, the domain scores range from 0 to 100, with higher scores indicative of greater impairment. Specific details on the scoring algorithms are provided by the developer in a user manual (Jones PW and Forde Y. St George’s respiratory questionnaire manual. 2009. Version 2.3).

In some instances, the subject comprises an extent of emphysema of <10%. Suitably the extent of damage to the air sacks is less than 10 %. Suitably the extent of emphysema in a subject is < 9%. Suitably the extent of emphysema in a subject is < 8%. Suitably the extent of emphysema in a subject is < 7%. Suitably the extent of emphysema in a subject is < 6%. Suitably the extent of emphysema in a subject is < 5%. Suitably, the extent of emphysema is measured before, suitably immediately prior to, administration of the effective amount of an IL-33 signalling axis antagonist.

In some instances, the BCSS score, the SGRQ score and the extent of emphysema are measured at baseline. The baseline may be the relevant value, level or score in a subject having COPD before administration of the effective amount of an IL-33 signalling axis antagonist. In some instances, the baseline is the relevant value, level or score in a subject immediately prior to said administration.

In some instances, the subject has had > 2 exacerbations in the previous 12 months prior to treatment. As defined herein an “exacerbation” of COPD may also be referred to as an acute exacerbation of COPD or “AECOPD” requiring systemic corticosteroids and/or antibiotics for at least 3 days duration (or 1 injection of depot formulation), or hospitalization for reason of AECOPD. The results show that subjects having had 2 or more exacerbations in the previous 12 months show improved response to treatment with tozorakimab (Figure 2).

Suitably, the subject may be equal to or over 40 years old. Suitably subject may be less than 80 years old. Suitably subject may be less than 75 years old. Suitably the subject may be between 40 and 75 years old. Suitably the subject may be between 40-45 years old, 45-50 years old, 50-55 years old, 55- 60 years old, 60-65 years old, 65-70 years old, or 70-75 years old. In one instance the subject is equal to or over 40 years old.

Suitably, the subject may be up to date with vaccines, suitably with vaccines for respiratory diseases. Suitably the subject has received pneumococcus and influenza vaccines.

Suitably the subject may have received treatment for COPD, or is currently receiving treatment for COPD. Suitably the subject may have, or be receiving, a documented stable regimen of treatment for COPD. Suitably said treatment may comprise one or more currently available COPD medications. Suitably the subject may have received, or is currently receiving, a dual therapy or triple therapy treatment for COPD. Suitably said dual therapy treatment may comprise ICS + LABA or LABA + LAMA. Suitably said triple therapy may comprise ICS + LABA + LAMA. Suitably the subject may have received said treatment for > 3 months.

In some instances, the subject may have a post-bronchodilator FEVi/FVC < 0.70L and a postbronchodilator FEVi > 30% and < 80% predicted normal value mat baseline. “Baseline” refers to the measurement in the subject prior to administration of the therapy disclosed herein.

Suitably, the subject may have a documented history of > 1 or >2 moderate or severe acute exacerbation of COPD (AECOPD) requiring (i) systemic corticosteroids and/or antibiotics for at least 3 days duration (or one injection of depot formulation), or (ii) hospitalization for reason of AECOPD in the previous 12 months prior to administration with the therapy disclosed herein.

Suitably the subject may have a normal body mass index (BMI). Suitably therefore the subject may have a BMI of >19 kg/m² and < 35 kg/m². Suitably the subject may have a BMI of >19 kg/m² and < 30 kg/m², >19 kg/m² and < 25 kg/m².

Method of treatment and method of improvement of lung function

Suitably, treatment of a subject having COPD results in improving the lung function of the subject. Suitably therefore in any of the methods of treatment or medical uses described herein the treatment of COPD is effected by improving lung function of the subject.

In some instances the lung function of the subject may be compared to the lung function of a control subject. Suitably the control subject is a subject having COPD who has not received the IL-33 signalling axis antagonist (which may be a subject from a placebo group).

Suitably the improvement in lung function may be measured by pulmonary function tests such as spirometry and plethysmography. Suitably therefore, the improvement in lung function may be an improvement of any one of the following lung function parameters: forced vital capacity (FVC), forced expiratory capacity (FEV), forced expiratory flow, and peak expiratory flow (PEF) rate, of the subject compared to a control. In some instances, “improvement” of any of the succeeding lung function parameters means “higher”. In some instances, “control” refers to the value of the lung function parameter at baseline. “Baseline” refers to the measurement in the subject prior to administration of the therapy disclosed herein.

Accordingly, the improvement of the lung function may be an improvement in the lung function of the subject after administration of the IL-33 signalling axis antagonist compared to baseline, i.e. compared to before administration of the IL-33 signalling axis antagonist. Suitably therefore, the improvement in lung function may be any one of the following: a higher forced vital capacity (FVC), a higher forced expiratory capacity (FEV), a higher forced expiratory flow, and a higher peak expiratory flow rate (PEF), of the subject compared to the same baseline measurement in the same subject i.e. before administration of the IL-33 signalling axis antagonist. In some instances, treatment of a subject having COPD or improving lung function in a subject having COPD results in reversal of airway obstruction. Airway obstruction of a subject may be compared to the airway obstruction of the same subject before administration of the IL-33 signalling axis antagonist. Reversal of airway obstruction may be assessed by comparing the FEVi or FVC values before (pre) and/or after (post) administration of bronchodilator (BD). Suitably, reversal of airway obstruction comprises an improvement in FEVi after administration of bronchodilator. Suitably, reversal of airway obstruction comprises an improvement in FVC after administration of bronchodilator (i.e., an improvement in post-BD FVC).

In some instances, treatment of a subject having COPD, or improving lung function in a subject having COPD, may result in increasing pre-BD FEVi of the subject. Pre-BD FEVi of the subject may be compared to the pre-BD FEVi of a control subject having COPD who has not received the IL-33 signalling axis antagonist (such as a subject from a placebo group). Alternatively, pre-BD FEVi of the subject may be compared to the baseline pre-BD FEVi of the same subject i.e. before administration of the IL-33 signalling axis antagonist.

In some instances, treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD FEVi of the subject by at least 50 ml. Suitably treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre- BD FEVi of the subject by at least 50 ml compared to a control or to baseline. Suitably treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre- BD FEVi of the subject by at least 50 ml at 12 weeks after administration of the IL-33 signalling axis antagonist, compared to a control or to baseline. Suitably treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD FEVi of the subject by at least 50 ml at 28 weeks after administration of the IL-33 signalling axis antagonist, compared to a control or to baseline.

In some instances, treatment of a subject having COPD, or improving lung function in a subject having COPD, results in increasing pre-BD FEVi of the subject by at least 60 ml. Suitably treatment of a subject having COPD, or improving lung function in a subject having COPD, results in increasing pre- BD FEVi of the subject by at least 60 ml compared to a control or to baseline. Suitably treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre- BD FEVi of the subject by at least 60 ml at 12 weeks after administration of the IL-33 signalling axis antagonist, compared to a control or to baseline. Suitably treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD FEVi of the subject by at least 60 ml at 28 weeks after administration of the IL-33 signalling axis antagonist, compared to a control or to baseline. In some instances, treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD FEVi of the subject by at least 50ml, at least 51ml, at least 52ml, at least 53ml, at least 54ml, at least 55ml, at least 56ml, at least 57ml, at least 58mL or at least 59mL. Suitably treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD FEVi of the subject by at least 50ml, at least 51ml, at least 52ml, at least 53ml, at least 54ml, at least 55ml, at least 56ml, at least 57ml, at least 58mL or at least 59mL compared to a control or to baseline. Suitably treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD FEVi of the subject by at least 50ml, at least 51ml, at least 52ml, at least 53ml, at least 54ml, at least 55ml, at least 56ml, at least 57ml, at least 58mL or at least 59mL at 12 weeks after administration of the IL-33 signalling axis antagonist, compared to a control or to baseline. Suitably treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD FEVi of the subject by at least 50ml, at least 51ml, at least 52ml, at least 53ml, at least 54ml, at least 55ml, at least 56ml, at least 57ml, at least 58mL or at least 59mL at 28 weeks after administration of the IL-33 signalling axis antagonist, compared to a control or to baseline.

In some instances, treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD FEVi of the subject by at least 61ml, at least 62ml, at least 63ml, at least 64ml, at least 65ml, at least 66ml, at least 70ml, at least 71ml, at least 72ml, at least 73ml, at least 74ml, at least 75ml, at least 76ml, at least 77ml, at least 78ml, at least 79ml, or at least 80ml. Suitably treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD FEVi of the subject by at least 60 ml, at least 61ml, at least 62ml, at least 63ml, at least 64ml, at least 65ml, at least 66ml, at least 70ml, at least 71ml, at least 72ml, at least 73ml, at least 74ml, at least 75ml, at least 76ml, at least 77ml, at least 78ml, at least 79ml, or at least 80ml compared to a control or to baseline. Suitably treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD FEVi of the subject by at least 60 ml, at least 61ml, at least 62ml, at least 63ml, at least 64ml, at least 65ml, at least 66ml, at least 70ml, at least 71ml, at least 72ml, at least 73ml, at least 74ml, at least 75ml, at least 76ml, at least 77ml, at least 78ml, at least 79ml, or at least 80ml at 12 weeks after administration of the IL-33 signalling axis antagonist, compared to a control or to baseline. Suitably treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD FEVi of the subject by at least 60ml, at least 61ml, at least 62ml, at least 63ml, at least 64ml, at least 65ml, at least 66ml, at least 70ml, at least 71ml, at least 72ml, at least 73ml, at least 74ml, at least 75ml, at least 76ml, at least 77ml, at least 78ml, at least 79ml, or at least 80ml at 28 weeks after administration of the IL-33 signalling axis antagonist, compared to a control or to baseline.

In some instances, the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FEVi of the subject by at least 80 ml. Suitably, the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FEVi of the subject by at least 80 ml compared to a control or to baseline. Suitably, the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FEVi of the subject by at least 80 ml at 12 weeks after administration of the IL- 33 signalling axis antagonist, compared to a control or to baseline. Suitably, the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD- FEVi of the subject by at least 80 ml at 28 weeks after administration of the IL-33 signalling axis antagonist, compared to a control or to baseline.

In some instances, the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FEVi of the subject by about 80 ml compared to a control or to baseline. Suitably, the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FEVi of the subject by about 80 ml compared to a control or to baseline. Suitably, the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FEVi of the subject by about 80 ml at 12 weeks after administration of the IL-33 signalling axis antagonist, compared to a control or to baseline. Suitably, the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FEVi of the subject by about 80 ml at 28 weeks after administration of the IL- 33 signalling axis antagonist, compared to a control or to baseline.

In some instances, treatment of a subject having COPD, or improving lung function in a subject having COPD, may result in increasing post-BD FEVi of the subject. Post-BD FEVi of the subject may be compared to the post-BD FEVi of a control subject having COPD who has not received the IL-33 signalling axis antagonist (such as a subject from a placebo group). Alternatively, post-BD FEVi of the subject may be compared to the baseline post-BD FEVi of the same subject i.e. before administration of the IL-33 signalling axis antagonist.

In some instances, the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FEVi of the subject by at least 60 ml. Suitably treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FEVi of the subject by at least 60 ml compared to a control or to baseline. Suitably treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FEVi of the subject by at least 60 ml at 12 weeks after administration of the IL-33 signalling axis antagonist, compared to a control or to baseline. Suitably treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FEVi of the subject by at least 80 ml at 28 weeks after administration of the IL-33 signalling axis antagonist, compared to a control or to baseline. Suitably treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FEVi of the subject by at least 90 ml at 28 weeks after administration of the IL-33 signalling axis antagonist, compared to a control or to baseline.

In some instances, the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FEV i of the subj ect by at least 60ml, at least 61 ml, at least

62ml, at least 63ml, at least 64ml, at least 65ml, at least 66ml, at least 70ml, at least 71ml, at least

72ml, at least 73ml, at least 74ml, at least 75ml, at least 76ml, at least 77ml, at least 78ml, at least

79ml, at least 80ml, at least 81ml, at least 82ml, at least 83ml, at least 84ml, at least 85ml, at least

86ml, at least 87ml, at least 88ml, at least 89ml, or at least 90ml. Suitably treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FEVi of the subject by at least 60 ml, at least 61ml, at least 62ml, at least 63ml, at least 64ml, at least 65ml, at least 66ml, at least 70ml, at least 71ml, at least 72ml, at least 73ml, at least 74ml, at least 75ml, at least 76ml, at least 77ml, at least 78ml, at least 79ml, at least 80ml, at least 81ml, at least 82ml, at least 83ml, at least 84ml, at least 85ml, at least 86ml, at least 87ml, at least 88ml, at least 89ml, or at least 90ml compared to a control or to baseline. Suitably treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FEVi of the subject by at least 60 ml, at least 61ml, at least 62ml, at least 63ml, at least 64ml, at least 65ml, at least 66ml, at least

70ml, at least 71ml, at least 72ml, at least 73ml, at least 74ml, at least 75ml, at least 76ml, at least

77ml, at least 78ml, at least 79ml, at least 80ml, at least 81ml, at least 82ml, at least 83ml, at least

84ml, at least 85ml, at least 86ml, at least 87ml, at least 88ml, at least 89ml, or at least 90ml at 12 weeks after administration of the IL-33 signalling axis antagonist, compared to a control or to baseline.

In some instances, the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FEVi of the subject by about 80ml or 90ml. Suitably, treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FEVi of the subject by about 80ml or 90 ml, compared to a control or to baseline. Suitably, treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FEVi of the subject by about 80ml at 12 weeks after administration of the IL-33 signalling axis antagonist, compared to a control or to baseline. Suitably, treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post- BD-FEVi of the subject by about 90 ml at 28 weeks after administration of the IL-33 signalling axis antagonist, compared to a control or to baseline.

In some instances, the increase in pre-BD-FEVi or post-BD-FEVi of the subject is achieved by week 12 after administration of an effective amount of the IL-33 signalling axis antagonist. In some instances, the increase in pre-BD-FEVi or post-BD-FEVi of the subject is achieved by week 28 after administration of an effective amount of the IL-33 signalling axis antagonist. In some instances, the treatment of a subject having COPD, or improving lung function in a subject having COPD, may result in increasing pre-BD FVC of the subject. Pre-BD FVC of the subjects may be compared to the pre-BD FVC of a control subject having COPD who has not received the IL-33 signalling axis antagonist (such as a subject from a placebo group). Alternatively, pre-BD FVC of the subject may be compared to the pre-BD FVC of the same subject at baseline, i.e. before administration of the IL-33 signalling axis antagonist.

In some instances, the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FVC of the subject by at least 60 ml. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FVC of the subject by at least 60 ml, compared to a control or to baseline. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FVC of the subject by at least 60 ml at 12 weeks after administration of an effective amount of the IL-33 signalling axis antagonist, compared to a control or to baseline. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FVC of the subject by at least 60 ml at 28 weeks after administration of an effective amount of the IL-33 signalling axis antagonist, compared to a control or to baseline.

In some instances, the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FVC of the subject by at least 60 ml, at least 61ml, at least 62ml, at least 63ml, at least 64ml, at least 65ml, at least 66ml, at least 70ml, at least 71ml, at least 72ml, at least 73ml, at least 74ml, at least 75ml, at least 76ml, at least 77ml, at least 78ml, at least 79ml, or at least 80ml. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FVC of the subject by at least 60 ml, at least 61ml, at least 62ml, at least 63ml, at least 64ml, at least 65ml, at least 66ml, at least 70ml, at least 71ml, at least 72ml, at least 73ml, at least 74ml, at least 75ml, at least 76ml, at least 77ml, at least 78ml, at least 79ml, or at least 80ml, compared to a control or to baseline. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FVC of the subject by at least 60 ml, at least 61ml, at least 62ml, at least 63ml, at least 64ml, at least 65ml, at least 66ml, at least 70ml, at least 71ml, at least 72ml, at least 73ml, at least 74ml, at least 75ml, at least 76ml, at least 77ml, at least 78ml, at least 79ml, or at least 80ml, at 12 weeks after administration of an effective amount of the IL-33 signalling axis antagonist, compared to a control or to baseline. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FVC of the subject by at least 60 ml, at least 61ml, at least 62ml, at least 63ml, at least 64ml, at least 65ml, at least 66ml, at least 70ml, at least 71ml, at least 72ml, at least 73ml, at least 74ml, at least 75ml, at least 76ml, at least 77ml, at least 78ml, at least 79ml, or at least 80ml, at 28 weeks after administration of an effective amount of the IL-33 signalling axis antagonist, compared to a control or to baseline. In some instances, the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FVC of the subject by at least 70 ml. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FVC of the subject by at least 70 ml, compared to a control or to baseline. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FVC of the subject by at least 70 ml at 12 weeks after administration of an effective amount of the IL-33 signalling axis antagonist, compared to a control or to baseline. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FVC of the subject by at least 70 ml at 28 weeks after administration of an effective amount of the IL-33 signalling axis antagonist, compared to a control or to baseline.

In some instances, the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FVC of the subject by about 70 ml. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FVC of the subject by about 70 ml, compared to a control or to baseline. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FVC of the subject by about 70 ml at 12 weeks after administration of an effective amount of the IL-33 signalling axis antagonist, compared to a control or to baseline. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre- BD-FVC of the subject by about 70 ml at 28 weeks after administration of an effective amount of the IL-33 signalling axis antagonist, compared to a control or to baseline.

Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FVC of the subject by about 80 ml. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FVC of the subject by about 80 ml, compared to a control or to baseline. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FVC of the subject by about 80 ml at 12 weeks after administration of an effective amount of the IL-33 signalling axis antagonist, compared to a control or to baseline. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing pre-BD-FVC of the subject by about 80 ml at 28 weeks after administration of an effective amount of the IL-33 signalling axis antagonist, compared to a control or to baseline.

In one instance, treatment of a subject having COPD, or improving lung function in a subject having COPD, may result in increasing post-BD FVC of the subject. Post-BD FVC of the subject may be compared to the post-BD FVC of a control subject having COPD who has not received the IL-33 signalling axis antagonist (such as a subject from a placebo group). Alternatively post-BD FVC of the subject may be compared to the post-BD FVC of the same subject at baseline i.e. before administration of the IL-33 signalling axis antagonist.

In some instances, the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FVC of the subject by at least 40 ml. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FVC of the subject by at least 40 ml, compared to a control or to baseline. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FVC of the subject by at least 40 ml at 12 weeks after administration of an effective amount of the IL-33 signalling axis antagonist, compared to a control or to baseline. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FVC of the subject by at least 40 ml at 28 weeks after administration of an effective amount of the IL-33 signalling axis antagonist, compared to a control or to baseline.

In some instances, the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FVC of the subject by at least 40 ml, at least 41ml, at least 42ml, at least 43ml, at least 44ml, at least 45ml, at least 46ml, at least 47ml, at least 48ml, at least 49ml, at least 50ml, at least 51ml, at least 52ml, at least 53ml, at least 54ml, at least 55ml, at least 56ml, at least 57ml, at least 58ml, at least 59ml, or at least 60ml. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD- FVC of the subject by at least 40 ml, at least 41ml, at least 42ml, at least 43ml, at least 44ml, at least 45ml, at least 46ml, at least 47ml, at least 48ml, at least 49ml, at least 50ml, at least 51ml, at least 52ml, at least 53ml, at least 54ml, at least 55ml, at least 56ml, at least 57ml, at least 58ml, at least 59ml, or at least 60ml compared to a control or to baseline. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FVC of the subject by at least 40 ml, at least 41ml, at least 42ml, at least 43ml, at least 44ml, at least 45ml, at least 46ml, at least 47ml, at least 48ml, at least 49ml, at least 50ml, at least 51ml, at least 52ml, at least 53ml, at least 54ml, at least 55ml, at least 56ml, at least 57ml, at least 58ml, at least 59ml, or at least 60ml at 12 weeks after administration of an effective amount of the IL-33 signalling axis antagonist, compared to a control or to baseline. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FVC of the subject by at least 40 ml, at least 41ml, at least 42ml, at least 43ml, at least 44ml, at least 45ml, at least 46ml, at least 47ml, at least 48ml, at least 49ml, at least 50ml, at least 51ml, at least 52ml, at least 53ml, at least 54ml, at least 55ml, at least 56ml, at least 57ml, at least 58ml, at least 59ml, or at least 60ml at 28 weeks after administration of an effective amount of the IL-33 signalling axis antagonist, compared to a control or to baseline. In some instances, the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FVC of the subject by about 60 ml. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FVC of the subject by about 60 ml, compared to a control or to baseline. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FVC of the subject by about 60 ml at 12 weeks after administration of an effective amount of the IL-33 signalling axis antagonist, compared to a control or to baseline. Suitably the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing post-BD-FVC of the subject by at about 60 ml at 28 weeks after administration of an effective amount of the IL-33 signalling axis antagonist, compared to a control or to baseline.

In some instances, the increase in pre-BD-FVC or post-BD-FVC of the subject is achieved by week 12 after administration of an effective amount of the IL-33 signalling axis antagonist. In some instances, the increase in pre-BD-FVC or post-BD-FVC of the subject is achieved by week 28 after administration of an effective amount of the IL-33 signalling axis antagonist.

In some instances, increasing pre-BD-FEVi, increasing post-BD-FEVi, increasing pre-BD-FVC, or increasing post-BD-FVC of the subject is relative to a baseline level. The baseline may be the level in a subject having COPD before administration of an effective amount of an IL-33 signalling axis antagonist. In some instances, the baseline is the level in the same subject prior to said administration of the effective amount of an IL-33 signalling axis antagonist.

In some instances, the treatment of a subject having COPD or improving lung function in a subject having COPD results in increasing the time-to-first CompEx event in the subject. Suitably therefore in any of the methods of treatment or medical uses described herein the treatment of COPD may be achieved by increasing the time-to-first CompEx event in the subject. Suitably the time to the first CompEx event is as measured after the administration of the IL-33 signalling axis antagonist.

In some instances, the time-to-first CompEx event in the subject, after administration of the IL-33 signalling axis antagonist, is increased by about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or by about 6 weeks relative to a control subject having COPD who has not received the IL-33 signalling axis antagonist. The time-to-first CompEx event in the subject may be increased by about 4 weeks, about 5 weeks, or about 6 weeks relative to a control subject having COPD who has not received the IL-33 signalling axis antagonist. Suitably, the time-to-first CompEx event in the subject is increased by at least 4 weeks compared to a subject from the placebo group. Suitably, the time-to-first CompEx event in the subject is increased by at least 5 weeks compared to a subject from the placebo group. Suitably, the time-to-first CompEx event in the subject is increased by at least 6 weeks compared to a subject from the placebo group. In some instances, the treatment of a subject having COPD or improving lung function in a subject having COPD results in reducing the rate of CompEx events in a subject having COPD, after administration of the IL-33 signalling axis antagonist. In some instances, the rate of CompEx events is reduced by at least 10%, 15%, 20%, 25%, or by at least 27%. Suitably the rate of CompEx events is reduced by at least 20%, or by at least 25%, or by at least 27%. Suitably the rate of CompEx events is reduced by at least 10%, 15%, 20%, 25%, or by at least 27% compared to the rate of CompEx events of a control subject having COPD who has not received the IL-33 signalling axis antagonist. Suitably the rate of CompEx events is reduced by at least 20%, by at least 25%, by at least 27% compared to the rate of CompEx events of a control subject having COPD who has not received the IL-33 signalling axis antagonist. Suitably the rate of CompEx events is reduced by at least 10%, 15%, 20%, 25%, or by at least 27%, suitably by at least 20%, by at least 25%, by at least 27%, compared to a subject from the placebo group. Alternatively, the rate of CompEx events is reduced by at least 10%, 15%, 20%, 25%, or by at least 27%, suitably by at least 20%, by at least 25%, by at least 27%, compared to the rate of CompEx events in the same subject prior to administration of the IL-33 signalling axis antagonist, suitably during the 12 months preceding the administration of the IL-33 signalling axis antagonist.

Suitably the time-to-first CompEx event and/or the rate of CompEx events after administration of an effective amount of the IL-33 signalling axis antagonist is compared to the time-to-first CompEx event and/or the rate of CompEx events of a control subject or a group of control subjects having COPD who have not received the IL-33 signalling axis antagonist, suitably which may be the placebo group. Suitably the rate of CompEx events after administration of an effective amount of the IL-33 signalling axis antagonist is compared to the rate of CompEx events of the same subject during the 12 months preceding the administration of the IL-33 signalling axis antagonist.

In some instances, the rate of CompEx events is reduced over a 28 week period after administration of an effective amount of the IL-33 signalling axis antagonist. Suitably the time-to-first CompEx event is increased over a 28 week period after administration of an effective amount of the IL-33 signalling axis antagonist. Suitably the reduction in the rate of CompEx events is achieved by week 28 after administration of an effective amount of the IL-33 signalling axis antagonist. Suitably the increase in time-to-first CompEx events is achieved by week 28 after administration of an effective amount of the IL-33 signalling axis antagonist.

Selecting a subject

This disclosure is furthermore related to a method of selecting a subject having COPD for treatment. Suitably any other method according to the present disclosure may further comprise a step of selecting a subject. The methods according to the present disclosure may involve selecting a subgroup of subjects who may benefit more from administration of the IL-33 signalling axis antagonist compared to simply any subject. Suitably the method of selecting a subject having COPD for treatment comprises a step of measuring the blood eosinophil count of the subject, suitably in a sample obtained from the subject. Suitably the sample is a blood sample. Suitably the blood eosinophil count may be measured using techniques known in the art. Suitably the blood eosinophil count may be referred to herein as EOC or EOS. Suitably the method of selecting a subject having COPD for treatment may further comprise an initial step of taking or obtaining a sample from the subject. Suitably taking or obtaining a blood sample from the subject. Suitably said sample is taken or obtained from the subject prior to administration of the IL-33 signalling axis antagonist, suitably immediately prior to administration of the IL-33 signalling axis antagonist.

Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <300 to > 150 cells/pl. Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <300 to > 150 cells/pl and if they are current or former smoker.

Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <290 to > 150 cells/pl. Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <280 to > 150 cells/pl. Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <270 to > 150 cells/pl. Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <260 to > 150 cells/pl.

Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <290 to > 150 cells/pl. Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <280 to > 150 cells/pl. Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <270 to > 150 cells/pl and are current or former smokers. Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <260 to > 150 cells/pl and are current or former smokers.

Suitably, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <250 to > 150 cells/pl. In some instances, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <250 to > 150 cells/pl and are current or former smokers.

Suitably, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <240 to > 150 cells/pl. In some instances, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <240 to > 150 cells/pl and are current or former smokers.

Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <230 to > 150 cells/pl. Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <220 to > 150 cells/pl. Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <210 to > 150 cells/pl. Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <200 to > 150 cells/pl.

Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <230 to > 150 cells/pl and are current or former smokers. Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <220 to > 150 cells/pl and are current or former smokers. Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <210 to > 150 cells/pl and are current or former smokers. Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <200 to > 150 cells/pl and are current or former smokers.

In some instances, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of < 300, < 290, < 280, < 270, < 260, < 250,

< 240, < 230, < 220, < 210, < 200 cells/pl of the IL-33 signalling axis antagonist. In some instances, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of < 300, < 290, < 280, < 270, < 260, < 250, < 240, < 230, < 220,

< 210, < 200 cells/pl of the IL-33 signalling axis antagonist and are current or former smokers.

In some instances, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of < 250 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist. In some instances, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of < 250 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist and are current or former smokers. In some instances, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from < 250 to > 150 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist. In some instances, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from < 250 to > 150 cells/ .1, (suitably which does not include 250 cells/ .1) of the IL-33 signalling axis antagonist and are current or former smokers.

In some instances, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of < 240 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist. In some instances, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of < 240 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist and are current or former smokers. In some instances, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from < 240 to > 150 cells/pl, (suitably which does not include 240 cells/pl) of the IL-33 signalling axis antagonist. In some instances, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from < 240 to > 150 cells/pl, (suitably which does not include 240 cells/pl) of the IL-33 signalling axis antagonist who are current or former smokers.

Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <290 to > 150 cells/pl and are current smokers. Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <280 to > 150 cells/pl and are current smokers. Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <270 to > 150 cells/pl and are current smokers. Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <260 to > 150 cells/pl and are current smokers.

In some instances, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <250 to > 150 cells/pl and are current smokers. In some instances, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <240 to > 150 cells/pl and are current smokers.

Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <230 to > 150 cells/pl and are current smokers. Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <220 to > 150 cells/pl and are current smokers. Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <210 to > 150 cells/pl and are current smokers. Suitably the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from <200 to > 150 cells/pl and are current smokers. In some instances, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of < 300, < 290, < 280, < 270, < 260, < 250, < 240, < 230, < 220, < 210, < 200 cells/pl of the IL-33 signalling axis antagonist and are current smokers.

In some instances, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of < 250 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist and are current smokers. In some instances, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from < 250 to > 150 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist and are current smokers.

In some instances, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of < 240 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist and are current smokers. In some instances, the method of selecting a subject having COPD for treatment comprises a step of selecting a subject if they have a blood eosinophil count of from < 240 to > 150 cells/pl, (suitably which does not include 240 cells/pl) of the IL-33 signalling axis antagonist who are current smokers.

Suitably a subject having COPD may be selected for treatment with an effective amount of an IL-33 signalling axis antagonist if the subject has, in addition to the requisite blood eosinophil count described herein, one or more further selection criteria which have been defined hereinabove. Suitably therefore the subject having COPD may be selected for treatment with an effective amount of an IL- 33 signalling axis antagonist if they have one or more of the characteristics as defined under the subsection of the ‘subject’ herein. Suitably therefore the methods for selecting a subject having COPD for treatment with an effective amount of an IL-33 signalling axis antagonist may comprise selecting said subject for treatment if the subject has:

(i) one or more further respiratory diseases or conditions such as chronic bronchitis, as may be defined bronchitis as defined as presence of cough and sputum on most days for > 3 months/year in at least the 2 years prior to receiving the treatment disclosed herein;

(ii) If the subject has had 1 or more AECOPD in the 12 months prior to receiving the treatment disclosed herein;

(iii) If the subject is over 40 years old

(iv) If the subject current or ex-smoker and has a tobacco history of > 5 pack-years, > 6 pack- years, > 7 pack-years, > 8 pack-years, > 9 pack-years, or > 10 pack-years;

(v) If the subject has received treatment for COPD, or is currently receiving treatment for COPD, such as documented stable regimen of dual therapy or triple therapy, which are described elsewhere herein; and/or (vi) If the subject has a normal body mass index (BMI), such as a BMI of >19 kg/m² and < 35 kg/m²

In some instances, the subject may be selected for treatment with an effective amount of an IL-33 signalling axis antagonist if the subject further comprises a BCSS score of around 7 or higher, 7.1 or higher, 7.2 or higher, 7.3 or higher, 7.4 or higher, 7.429 or higher. BCSS score is defined hereinabove.

In some instances the subject may be selected for treatment with an effective amount of an IL-33 signalling axis antagonist if the subject further comprises a SGRQ score of around 58 or higher, 58.1 or higher, 58.2 or higher, 58.239 or higher. SGRQ score is defined hereinabove.

In some instances, the subject may be selected for treatment with an effective amount of an IL-33 signalling axis antagonist if the subject further comprises an extent of emphysema of <10%.

In some instances, the subject may be selected for treatment with an effective amount of an IL-33 signalling axis antagonist if the subject has had 2 or more AECOPD in the 12 months prior to treatment.

In some instances, the subject may be selected for treatment with an effective amount of an IL-33 signalling axis antagonist if the subject has had 2 or more moderate AECOPD and/or one or more severe AECOPD in the 12 months prior to treatment.

The results from FRONTIER-4 presented in the examples show that subjects having COPD and one or more of these additional criteria show numerically superior improvements in clinical pre-BD FEVi compared to those subjects who received therapy but did not meet one or more of these additional criteria (see Figure 2).

Suitably any one or more of the above selection criteria may additionally be applied in a method of selecting a subject having COPD for treatment with an effective amount of an IL-33 signalling axis antagonist. Suitably any one or more of the above selection criteria may comprise the features described in more detail above in the section ‘subject’, and may be applied herein in a method of selecting a subject having COPD for treatment with an effective amount of an IL-33 signalling axis antagonist.

Suitably once the subject is selected for treatment, the subject is then treated by administration of an effective amount of the IL-33 signalling axis antagonist. Suitably the selection methods may comprise a step of administering an effective amount of an effective amount of an IL-33 signalling axis antagonist to said subject, suitably to treat said subject. Suitable IL-33 signalling axis antagonist, effective amounts and routes of administration are defined elsewhere herein. Suitably the method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <300 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist. In some instances, the method according to any aspect of the present disclosure comprises a step of selecting a subject having a blood eosinophil count of from <300 to > 150 cells/pl prior to said administration.

The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <300 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <290 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <280 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <270 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <260 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist.

The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of < 300, < 290, < 280, < 270, < 260, < 250, < 240, < 230, < 220, < 210, < 200 cells/pl of the IL-33 signalling axis antagonist.

The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of < 250 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from < 250 to > 150 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist.

The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of < 240 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from < 240 to > 150 cells/pl, (suitably which does not include 240 cells/pl) of the IL-33 signalling axis antagonist.

The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <300 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <290 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <280 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <270 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <260 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers.

In some instances, the method according to any aspect of the present disclosure comprises a step of selecting a subject having a blood eosinophil count of from <250 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers. In some instances, the method according to any aspect of the present disclosure comprises a step of selecting a subject having a blood eosinophil count of from <240 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers.

The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <230 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <220 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <220 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <210 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <200 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current or former smokers.

The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of < 300, < 290, < 280, < 270, < 260, < 250, < 240, < 230, < 220, < 210, < 200 cells/pl of the IL-33 signalling axis antagonist who are current or former smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of < 250 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist who are current or former smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from < 250 to > 150 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist who are current or former smokers.

The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of < 240 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist who are current or former smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from < 240 to > 150 cells/pl, (suitably which does not include 240 cells/pl) of the IL-33 signalling axis antagonist who are current or former smokers.

The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <300 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <290 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <280 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <270 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <260 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers.

In some instances, the method according to any aspect of the present disclosure comprises a step of selecting a subject having a blood eosinophil count of from <250 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers. In some instances, the method according to any aspect of the present disclosure comprises a step of selecting a subject having a blood eosinophil count of from <240 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers.

The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <230 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <220 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <220 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <210 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from <200 to > 150 cells/pl prior to administration of the IL-33 signalling axis antagonist who are current smokers.

The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of < 300, < 290, < 280, < 270, < 260, < 250, < 240, < 230, < 220, < 210, < 200 cells/pl of the IL-33 signalling axis antagonist who are current smokers.

The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of < 250 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist who are current smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from

< 250 to > 150 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist who are current smokers.

The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of < 240 cells/pl, (suitably which does not include 250 cells/pl) of the IL-33 signalling axis antagonist who are current smokers. The method according to any aspect of the present disclosure may comprise a step of selecting a subject having a blood eosinophil count of from

< 240 to > 150 cells/pl, (suitably which does not include 240 cells/pl) of the IL-33 signalling axis antagonist who are current smokers.

CompEx event

The present disclosure also relates to a method of increasing the time-to-first CompEx event and to reducing the rate of CompEx events in subjects having COPD. Suitably, with reference to COPD herein, any ‘CompEx event’ may also be referred to as a ‘COPDCompEx event’. Therefore the present disclosure relates to a method of increasing the time-to-first COPDCompEx event and to reducing the rate of COPDCompEx events in subjects having COPD.

Suitably the term CompEx event refers to a composite endpoint for exacerbations, suitably herein for exacerbations in COPD. The CompEx event typically combines exacerbations with events defined from participant Diaries, suitably as defined below. Note the CompEx event definition typically includes dropout due to lack of efficacy as a CompEx event. However, in studies where Tack of efficacy’ is not listed as a reason for discontinuation, the drop out criterion for CompEx may not be included.

Suitably, a participant will be considered to have a CompEx event if the participant has one or more of the following:

• An exacerbation, with at least one of the following criteria met: o Associated Hospitalizations = Yes; o Systemic Corticosteroids (injected and/or oral) = Yes; o Antibiotics = Yes; and/or o Any emergency room visit due to COPD exacerbation? = Yes; and/or

• A diary event with objective deterioration, suitably which is defined as either the threshold criterion or the slope criterion (or both), being met for >2 consecutive days.

For this purpose, “2 consecutive days” means strictly the same 2 consecutive days when assessing multiple requirements within those days. For the Diary data (which is captured twice during the day), one day will be defined by the evening/moming pairing as the other Diary endpoints in this trial. Diary data recorded in the evening of day n and in the morning of day n+1 will belong to study day n.

The fulfilment of objective deterioration criteria will be calculated for each diary variable for threshold criterion and slope criterion, suitably which are defined as follows.

Suitably the threshold criterion comprise: a. > 12% decrease from baseline in morning PEF. b. > 1.75 doses increase from baseline in daily total rescue medication. Suitably one day is defined as evening/moming pairing. The number of doses of rescue medication is defined as the number of puffs of inhaler recorded in the evening and morning, respectively.) Suitably if either the evening or morning result is missing then the single non-missing result will be used. c. > 0.75 increase from baseline or having maximal symptom score 4 in at least one of the following symptom scores: breathlessness, cough, and sputum. Suitably having: i. > 0.75 increase from baseline or having maximal symptom score 4 in breathlessness daily score; ii. > 0.75 increase from baseline or having maximal symptom score 4 in cough daily score; or iii. > 0.75 increase from baseline or having maximal symptom score 4 in sputum daily score.

Suitably, the threshold criterion is met if [(a) or (b)] and at least one of (c) are met. Suitably on at least 2 consecutive days. Suitably on 2, 3, 4, 5, 6, or 7 consecutive days or more. Suitably, the slope criterion comprise: d. Morning PEF slopes < -3%/day. e. Daily total rescue medication slope > 0.4 doses/day f. Slope > 0.2/day in all of the following symptom score: breathlessness, cough, and sputum.

Suitably the slope criterion is met if [(d), (e) and (f)] are all met, and at least one of [(a), (b) or (c)] is met. Suitably wherein the slope criterion are determined from a regression slope generated from measurement of values of the above criteria in the preceding 5 -day rolling period.

In some instances, the time-to-first CompEx event in the subject is increased by about 1 week, 2 weeks, 3 weeks, 4 weeks, or by about 5 weeks, or by about 6 weeks relative to a control subject who has not received the IL-33 signalling axis antagonist. The time-to-first CompEx event in the subject may be increased by about 4 weeks, by about 5 weeks, by about 6 weeks relative to a control subject having COPD who has not received the IL-33 signalling axis antagonist. Suitably, the time-to-first CompEx event in the subject is increased by at least 4 weeks compared to a subject from the placebo group. Suitably, the time-to-first CompEx event in the subject is increased by at least 5 weeks compared to a subject from the placebo group. Suitably the time-to-first CompEx event in the subject is increased by at least 6 weeks compared to a subject from the placebo group.

In some instances, the rate of CompEx events in a subject or a group of subjects is reduced by at by at least 10%, 15%, 20%, 25%, or by at least 27%. In some instances, the rate of CompEx events in a subject or a group of subjects is reduced by at least 10%, 15%, 20%, 25%, or by at least 27%, suitably by at least 20%, or by at least 25% or by at least 27% after administration of an effective amount of the IL-33 signalling axis antagonist compared to a control subject or control group of subjects who have not received the IL-33 signalling axis antagonist. The rate of CompEx events in the subject may be reduced by at least 10%, 15%, 20%, 25%, or by at least 27%, suitably by at least 20%, by at least 25%, by at least 27% after administration of an effective amount of the IL-33 signalling axis antagonist compared to a control subject or group of subjects having COPD who have not received the IL-33 signalling axis antagonist.

Suitably the rate of CompEx events is reduced by at least 10%, 15%, 20%, 25%, or by at least 27%. Suitably the rate of CompEx events is reduced by at least 20%, by at least 25%, by at least 27% compared to the rate of CompEx events of a control subject having COPD who has not received the IL-33 signalling axis antagonist. Suitably the rate of CompEx events is reduced by at least 20%, by at least 25%, by at least 27% compared to the rate of CompEx events of a control subject having COPD who has not received the IL-33 signalling axis antagonist. Suitably the rate of CompEx events is reduced by at least 20%, by at least 25%, by at least 27% compared to a subject from the placebo group.

Suitably the time-to-first CompEx event and/or the rate of CompEx events after administration of an effective amount of the IL-33 signalling axis antagonist is compared to the time-to-first CompEx event and/or the rate of CompEx events of a control subject or a group of control subjects having COPD who have not received the IL-33 signalling axis antagonist, suitably which may be the placebo group.

IL-33 signalling axis antagonist

Suitably, the IL-33 signalling axis antagonist reduces, inhibits or neutralises IL-33 activity. Interleukin- 33 (IL-33), also known as IL-1F11, is a member of the interleukin-1 (IL-1) cytokine family that is encoded by the IL33 gene. IL-33 is a 270 amino acid protein consisting of two domains: a homeodomain and a cytokine (IL-1 like) domain. The homeodomain contains a nuclear localisation signal (NLS). IL-33 is known to exist in different forms; a reduced form (redIL-33) and an oxidised form (oxIL-33). Previous studies have shown that the reduced form is rapidly oxidised under physiological conditions to form at least one disulphide bond in the oxidised form, and that the two forms likely have different binding patterns and effects.

IL-33 is constitutively expressed in multiple cell types, including structural cells, such as smooth muscle, epithelial, and endothelial cells. It has been reported that IL-33 expression can also be induced by inflammatory factors in macrophages and dendritic cells. Cellular stress caused by environmental triggers, such as allergens, toxins, and pathogens, and mechanistic insult can lead to IL-33 release. Free IL-33 associates with a heterodimeric IL-33 receptor complex composed of suppression of tumorigenicity 2 (ST2) protein and interleukin- 1 receptor accessory protein (IL-1 RacP) to activate the AP-1 and NF-KB pathways through the adaptor protein myeloid differentiation primary response 88 (MyD88) and possibly MyD88-adapter-like (Mai) protein. IL-33 stimulates numerous cell types, including innate lymphoid type II cells (ILC2), mast cells, basophils, eosinophils, and dendritic cells, to promote an immune response. It was previously discovered that the reduced form of IL-33 binds to ST2, and is in fact the only known ligand of the ST2 receptor expressed by Th2 cells and mast cells. Soluble ST2 (sST2) is thought to be a decoy receptor that prevents reduced-IL-33 signalling. The terms "interleukin 1 receptor-like 1 (IL1RL” )" and "ST2" used interchangeably herein, refer to any native ST2 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. ST2 is also referred to in the art as DER4, Tl, and FIT-1. The term encompasses "full-length," unprocessed ST2, as well as any form of ST2 that results from processing in the cell. At least four isoforms of ST2 are known in the art, including soluble (sST2, also known as IL 1 RL 1-a) and transmembrane (ST2L, also known as IL 1 RL 1-b), which arise from differential mRNA expression from a dual promoter system, and ST2V and ST2LV, which arise from alternative splicing. The domain structure of ST2L includes three extracellular immunoglobulin-like C2 domains, a transmembrane domain, and a cytoplasmic Toll/lnterleukin-1 receptor (TIR) domain. sST2 lacks the transmembrane and cytoplasmic domains contained within ST2L and includes a unique 9 amino acid (a. a.) C-terminal sequence (see, e.g., Kakkar et al. Nat. Rev. Drug Disc.40 7: 827-840, 2008). sST2 can function as a decoy receptor to inhibit soluble IL-33. The term also encompasses naturally occurring variants of ST2, e.g., splice variants (e.g., ST2V, which lacks the third immunoglobulin motif and has a unique hydrophobic tail, and ST2LV, which lacks the transmembrane domain of ST2L) or allelic variants (e.g., variants that are protective against COPD risk or that confer COPD risk as described herein). The amino acid sequence of an exemplary human ST2 can be found, for example, under UniProtKB accession number 001638. ST2 is a part of the IL- 33 receptor along with the co-receptor protein IL-1 RacP. Binding of IL-33 to ST2 and the co-receptor interleukin- 1 receptor accessory protein (IL-1 RacP) forms a 1:1:1 ternary signalling complex to promote downstream signal transduction (Lingel et al. Structure 17(10): 1398-1410,2009, and Liu et al. Proc. Nat. Acad. Sci. 11 0(37): 14918-14924, 2013).

‘ST2 pathway’ as employed herein refers to the IL-33/ST2 system where reduced IL-33 recognition by ST2 promotes dimerization with IL-lRAcP on the cell surface and within the cell recruitment of receptor complex components MyD88, TRAF6 and IRAKI -4 to intracellular TIR domain. Thus ST2 dependent signalling/effects may be interrupted and attenuated by perturbing the interaction of IL-33 with ST2 or alternatively by interrupting the interaction with IL-lRAcP.

It is contemplated herein that antibodies, binding fragments, or antibody variants that specifically bind to and inhibit components of the IL-33 signalling axis may be useful for the treatment of COPD.

Suitably the IL-33 signalling axis antagonist is an antibody, variant or antigen binding fragment thereof which specifically binds to and inhibits one or more components of the IL-33/ST2 signalling axis. Suitably the IL-33 signalling axis antagonist is an antibody, variant or antigen binding fragment thereof which specifically binds to and inhibits the IL-33 receptor complex. Suitably the IL-33 signalling axis antagonist is an antibody, variant or antigen binding fragment thereof which specifically binds to and inhibits ST2. Suitably the IL-33 signalling axis antagonist is an antibody, variant or antigen binding fragment thereof which specifically binds to and inhibits IL-1 RacP. In some instances, the IL-33 signalling axis antagonist binds to and inhibits reduced IL-33. In some instances, the IL-33 signalling axis antagonist is an antibody, variant or antigen binding fragment thereof which specifically binds to and inhibits reduced IL-33. In some instances, the IL-33 signalling axis antagonist binds to and inhibits oxidised IL-33. In some instances, the IL-33 signalling axis antagonist is an antibody, variant or antigen binding fragment thereof which specifically binds to and inhibits oxidised IL-33. In some instances, the IL-33 signalling axis antagonist specifically binds to and inhibits both reduced and oxidised IL-33. In some instances, the IL-33 signalling axis antagonist is an antibody, variant or antigen binding fragment thereof which specifically binds to and inhibits both reduced and oxidised IL-33. In some instances, the IL-33 signalling axis antagonist binds to and inhibits reduced IL-33, and inhibits the conversion of reduced IL-33 into oxidised IL-33. In some instances, the IL-33 signalling axis antagonist is an antibody, variant or antigen binding fragment thereof which specifically binds to and inhibits reduced IL-33, and inhibits the conversion of reduced IL-33 into oxidised IL-33.

Suitably, therefore, the IL-33 signalling axis antagonist used herein is a binding molecule which may be selected from: an antibody, an antigen-binding fragment thereof, an aptamer, at least one heavy or light chain CDR of a reference antibody molecule, and at least six CDRs from one or more reference antibody molecules.

In some instances, the IL-33 signalling axis antagonist is an antibody, or variant thereof i.e. any antibody that binds specifically to and inhibits IL-33, which is effective in the treatment of COPD.

Suitably, the antibody or antigen binding fragment thereof is selected from: naturally-occurring, polyclonal, monoclonal (Mabs), recombinant, multispecific, mouse, human, humanized such as complementarity-determining region (CDR)-grafted, primatized, chimeric, and antibody variants, including single chain, monomeric antibodies, and/or bispecific, as well as fragments or derivatives thereof.

Suitably, the IL-33 signal axis antagonist is an antibody or an antigen binding fragment thereof. Suitably, the antigen binding fragment may be an epitope-binding fragment, e.g., Fab’ and F(ab’)2, Fd, Fvs, single-chain Fvs (scFv), disulfide-linked Fvs (sdFv), fragments comprising either a VL or VH domain, or fragments produced by a Fab expression library. Suitably the Fab and F’ab') fragments may be generated by enzymatic cleavage of full-length antibodies. Other antigen binding fragments include those generated by recombinant DNA techniques, such as the expression of recombinant plasmids containing nucleic acid sequences encoding antibody variable regions. Suitably, t’e antibody or antigen binding fragment thereof may be a minibody, a diabody, a triabody, a tetrabody, or a single chain antibody. Suitably, the antibody or antigen binding fragment thereof is a monoclonal antibody. ScFv molecules are known in the art and are described, e.g., in U.S. Pat. No. 5,892,019. In some instances, the anti -IL-33 antibody variant or antigen binding fragment thereof is selected from the group consisting of a diabody, a triabody, a tetrabody, a Fab fragment, single domain antibody, scFv, wherein the dose is adjusted such that the binding sites to be equimolar to those dosed by bivalent antibodies.

Monoclonal antibodies may be modified for use as therapeutics or diagnostic". "Monoclonal antibody" “r "monoclonal antibody composition" as used herein refers to polypeptides, including antibodies, bispecific antibodies, etc., that have substantially identical amino acid sequence or are derived from the same genetic source. This term also includes preparations of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.

One instance is a "chimeric" antibody in which a portion of the heavy (H) and/or light (L) chain is identical with or homologous to a corresponding sequence in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is/are identical with or homologous to a corresponding sequence in antibodies derived from another species or belonging to another antibody class or subclass. Also included are fragments of such antibodies, so long as they exhibit the desired biological activity. See U.S. Pat. No. 4,816,567; Morrison et al., 1985, Proc. Natl. Acad. Sci. 81:6851-55.

In another instance, a monoclonal antibody is a "humanized" antibody. Methods for humanizing nonhuman antibodies are well known in the art. See U.S. Pat. Nos. 5,585,089 and 5,693,762. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source that is nonhuman. Humanization can be performed, for example, using methods described in the art (Jones et al., 1986, Nature 321 :522-25; Riechmann et al., 1998, Nature 332:323-27; Verhoeyen et al., 1988, Science 239:1534-36), by substituting at least a portion of a rodent complementarity-determining region for the corresponding regions of a human antibody.

Also contemplated are human antibodies and antibody variants (including antibody fragments) that bind to IL-33. Using transgenic animals (e.g., mice) that are capable of producing a repertoire ofhuman antibodies in the absence of endogenous immunoglobulin production such antibodies are produced by immunization with a polypeptide antigen (i.e., having at least 6 contiguous amino acids), optionally conjugated to a carrier. See, e.g., Jakobovits et al., 1993, Proc. Natl. Acad. Sci. 90:2551-55; Jakobovits et al., 1993, Nature 362:255-58; Bruggermann et al., 1993, Year in Immuno. 7:33. See also PCT App. Nos. PCT/US96/05928 and PCT/US93/06926. Additional methods are described in U.S. Pat. No. 5,545,807, PCT App. Nos. PCT/US91/245 and PCT/GB 89/01207, and in European Patent Nos. 54607381 and 546073 A 1. Human antibodies can also be produced by the expression of recombinant DNA in host cells or by expression in hybridoma cells as described herein.

Chimeric, CDR grafted, and humanized antibodies and/or antibody variants are typically produced by recombinant methods. Nucleic acids encoding the antibodies are introduced into host cells and expressed using materials and procedures described herein. In one instance, the antibodies are produced in mammalian host cells, such as CHO cells. Monoclonal (e.g., human) antibodies may be produced by the expression of recombinant DNA in host cells or by expression in hybridoma cells as described herein.

Immunoglobulin or antibody molecules of the disclosure can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2, etc.), or subclass of immunoglobulin molecule. In one instance, IL-33 signalling axis antagonist is an IgGl antibody, an lgG2 antibody, an lgG3 antibody, or an lgG4 antibody. In some instances, the IL-33 signalling axis antagonist useful in the present methods is a monoclonal IgGl antibody.

In some instances, the IL-33 signalling axis antagonist is an anti -IL-33 antibody, anti-ST2 antibody anti-ILl-RacP antibody, a binding fragment, or a variant thereof. Suitably, the anti-IL-33 antibody, variant, or binding fragment thereof specifically binds to IL-33, either reduced or oxidised IL-33.

In some instances, the IL-33 signalling axis antagonist is an anti -IL-33 antibody, binding fragment, or variant thereof. Suitably any anti -IL-33 antibody, binding fragment, or variant thereof may be used in the methods of the disclosure.

In some instances, the anti -IL-33 antibody, binding fragment, or antibody variant thereof binds to IL- 33 comprising an amino acid sequence of SEQ ID NO:45. In various instances, the anti-IL-33 antibody, binding fragment, or antibody variant thereof may be capable of binding to a mature form of the full- length IL-33 protein comprising an amino acid sequence of SEQ ID NO:45. In various instances, the anti -IL-33 antibody, binding fragment, or antibody variant thereof may be capable of binding to an IL- 33 protein fragment comprising amino acids 72-270, 79-270, 95-270, 99-270, 107-270, 109-270, 111- 270, or 112-270 of SEQ ID NO:45.

In various instances, the anti -IL-33 antibody, binding fragment, or antibody variant thereof may be capable of binding to the reduced (red-IL-33) and/or the oxidised (ox-IL-33) form of IL-33. In some instances, the anti -IL-33 antibody, binding fragment, or antibody variant thereof may be capable of preferentially binding to the reduced (red-IL-33) and/or the oxidised (ox-IL-33) form of IL-33.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof specifically binds to redIL-33 with a binding affinity (Kd) of less than 5 x 10'² M, 10'² M, 5 x 10'³ M, 10'³ M, 5 x 10'⁴ M, 10'⁴ M, 5 x 10'⁵ M, 10'⁵ M, 5 x 10'⁶ M, 10'⁶ M, 5 x 10'⁷ M, 10'⁷ M, 5 x 10'⁸ M, 10'⁸ M, 5 x 10'⁹ M, 10’ ⁹ M, 5 x IO’¹⁰ M, IO’¹⁰ M, 5 x 10’¹¹ M, 10’¹¹ M, 5 x IO’¹² M, IO’¹² M, 5 x IO’¹³ M, IO’¹³ M, 5 x IO’¹⁴ M, 10'¹⁴ M, 5 x IO'¹⁵ M, or 10'¹⁵ M. Suitably, the binding affinity to redIL-33 is less than 5 x 10'¹⁴M (i.e. 0.05 pM). Suitably, the binding affinity is as measured using Kinetic Exclusion Assays (KinExA) or BIACORE™, suitably using KinExA, using protocols such as those described in WO2016/156440 (see e.g., Example 11), which is hereby incorporated by reference in its entirety. Anti-IL-33 antibodies, binding fragments, or antibody variants thereof that bind to redIL-33 with this binding affinity appear to bind tightly enough to redIL-33 to prevent dissociation of the binding molecule/redIL-33 complex within biologically relevant timescales. Without wishing to be bound by theory, this binding strength is thought to prevent release of the antigen prior to degradation of the antibody/antigen complex in vivo, such that redIL-33 is not released and cannot undergo conversion from redIL-33 to oxIL-33. Thus, when binding to redIL-33 with this binding affinity, the anti -IL-33 antibody, binding fragment, or antibody variant thereof can inhibit or attenuate the activity of oxIL-33 by preventing its formation.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof may specifically bind to redIL-33 with an on rate (k(on)) of greater than or equal to 10³ M'¹ sec'¹, 5 X 10³ M'¹ sec'¹, 10⁴ M'¹ sec'¹ or 5 X 10⁴ M'¹ sec'¹. For example, anti-IL-33 antibody, binding fragment, or antibody variant thereof of the disclosure may bind to redIL-33 or a fragment or variant thereof with an on rate (k(on)) greater than or equal to 10⁵ M'¹ sec'¹, 5 X 10⁵ M'¹ sec'¹, 10⁶ M'¹ sec'¹, or 5 X 10⁶ IXT'sec'¹ or 10⁷ M' ^ec'¹. Suitably, the k(on) rate is greater than or equal to 10⁷ M^sec'¹.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof may specifically bind to redIL-33 with an off rate (k(off)) of less than or equal to 5 X 10'¹ sec'¹, 10'¹ sec'¹, 5 X 10'² sec'¹, 10' ² sec'¹, 5 X 10'³ sec'¹ or 1 O'³ sec'¹. For example, anti-IL-33 antibody, binding fragment, or antibody variant thereof of the disclosure may be said to bind to redIL-33 or a fragment or variant thereof with an off rate (k(off)) less than or equal to 5 X 10'⁴ sec'¹, 10'⁴ sec'¹, 5 X 10'⁵ sec'¹, 10'⁵ sec'¹, 5 X 10'⁶ sec' 10'⁶ sec'¹, 5 X 10'⁷ sec'¹ or 10'⁷ sec'¹. Suitably, the k(off) rate is less than or equal to 10'³ sec'¹. IL-33 is an alarmin cytokine released rapidly and in high concentrations in response to inflammatory stimuli. redIL-33 is converted to the oxidised approximately 5-45 mins after release into the extracellular environment. Thus, to prevent conversion of redIL-33 to oxIL-33, the anti -IL-33 antibody, binding fragment, or antibody variant thereof described herein may bind to redIL-33 with these k(on) and/or k(off) rates. Without wishing to be bound by theory, these k(on)/k(off) rates are thought to ensure that the anti -IL-33 antibody, binding fragment, or antibody variant thereof can bind rapidly to redIL-33 before it converts to oxIL-33, thereby reducing the formation of oxIL-33.

In various instances, the anti -IL-33 antibody, binding fragment, or antibody variant thereof may be an inhibitory antibody, capable of inhibiting IL-33 or a fragment thereof as defined herein. In various instances, an inhibitory antibody may be capable of inhibiting the association of IL-33 or a fragment thereof with the IL-33 receptor complex, ST2 and/or IL-1 RacP. Suitable anti -IL-33 antibodies for use in the methods of the disclosure are known in the art and may comprise any of the following anti-IL-33 antibodies: 33 640087-7B (as described in WO2016/156440), ANB020 known as Etokimab (as described in WO2015/106080), 9675P (as described in US2014/0271658), A25-3H04 (as described in US2017/0283494), Ab43 (as described in WO20 18/081075), IL33-158 (as described in US2018/0037644), 10C12.38.H6. 87Y.581 lgG4 (as described in WO2016/077381) or binding fragments thereof, QX007N (as described in WO2023029280) or binding fragments thereof, each of the documents being incorporated herein by reference. All of these antibodies are referenced in Table 1. Suitable anti-IL-33 antibodies for use in the methods of the disclosure are known in the art and may further comprise any of the following: TCQ-2938 (as described in WO2021/228091) or binding fragments thereof, 9MW1911 (as described in WO2021/147937) or binding fragments thereof, 621 (as described in WO2022/063281) or binding fragments thereof, in which the VH and VL domains are fully described and incorporated herein by reference.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises the complementarity determining regions (CDRs) of a variable heavy domain (VH) and a variable light domain (VL) pair selected from Table 1. Pair 1 corresponds to the VH and VL domain sequences of 33_640087-7B describedin WO2016/156440. 33_640087-7B is also referred to herein as tozorakimab. Pairs 2-7 correspond to VH and VL domain sequences of antibodies described in US2014/0271658. Pairs 8-12 correspond to VH and VL domain sequences of antibodies described in US2017/0283494. Pair 13 corresponds to the VH and VL domain sequences of ANB020, described in WO2015/106080. Pairs 14-16 correspond to VH and VL domain sequences of antibodies described in W02018/081075. Pair 17 corresponds to VH and VL domain sequences of IL33-158 described in US2018/0037644. Pair 18 corresponds to VH and VL domain sequences of 10C12.38.H6. 87Y.581 lgG4 described in WO20 16/077381.

Table 1: Exemplary anti-IL-33 antibody VH and VL pairs

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises the complementarity determining regions (CDRs) of the heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 1 and the complementarity determining regions (CDRs) of light chain variable region (VL) comprising the sequence of SEQ ID NO: 19. These CDRs correspond to those derived from Tozorakimab 33 640087-7B (as described in WO2016/156440), which binds reduced IL-33 and inhibits its conversion to oxidised IL-33. Tozorakimab or 33 640087-7B is described in full in WO2016/156440 which is incorporated by reference herein.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises the complementarity determining regions (CDRs) of the heavy chain variable region (VH) comprising the sequence of SEQ ID NO:7 and the complementarity determining regions (CDRs) of light chain variable region (VL) comprising the sequence of SEQ ID NO:25. These CDRs correspond to those derived from the antibody 9675P. 9675P is described in full in US2014/0271658 which is incorporated by reference herein.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises the complementarity determining regions (CDRs) of the heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 11 and the complementarity determining regions (CDRs) of light chain variable region (VL) comprising the sequence of SEQ ID NO:29. These CDRs correspond to those derived from the antibody A25-3H04. A25-3H04 is described in full in US2017/0283494 which is incorporated by reference herein.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises the complementarity determining regions (CDRs) of the heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 13 and the complementarity determining regions (CDRs) of light chain variable region (VL) comprising the sequence of SEQ ID NO:31. These CDRs correspond to those derived from the antibody ANB020. ANB020 is described in full in W02015/106080 which is incorporated by reference herein.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises the complementarity determining regions (CDRs) of the heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 16 and the complementarity determining regions (CDRs) of light chain variable region (VL) comprising the sequence of SEQ ID NO:34. These CDRs correspond to those derived from the antibody Ab43. Ab43 is described in full in W02018/081075 which is incorporated by reference herein.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises the complementarity determining regions (CDRs) of the heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 17 and the complementarity determining regions (CDRs) of light chain variable region (VL) comprising the sequence of SEQ ID NO:35. These CDRs correspond to those derived from the antibody IL33-158. IL33-158 is described in full in US2018/0037644 which is incorporated by reference herein.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises the complementarity determining regions (CDRs) of the heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 18 and the complementarity determining regions (CDRs) of light chain variable region (VL) comprising the sequence of SEQ ID NO:36. These CDRs correspond to those derived from the antibody 10C12.38.H6. 87Y.581 lgG4. 10C12.38.H6. 87Y.581 lgG4 is described in full in WO2016/077381 which is incorporated by reference herein.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises the complementarity determining regions (CDRs) of the heavy chain variable region (VH) comprising the sequence of SEQ ID NO:46 and the complementarity determining regions (CDRs) of light chain variable region (VL) comprising the sequence of SEQ ID NO:47. These CDRs correspond to those derived from the antibody QX007N. QX007N is described in full in W02023/029280 which is incorporated by reference herein.

Suitably the skilled person knows of available methods in the art to identify CDRs within the heavy and light variable regions of an antibody or antigen-binding fragment thereof. Suitably the skilled person may conduct sequence-based annotation, for example. The regions between CDRs are generally highly conserved, and therefore, logic rules can be used to determine CDR location. The skilled person may use a set of sequence-based rules for conventional antibodies (Pantazes and Maranas, Protein Engineering, Design and Selection, 2010), alternatively or additionally he may refine the rules based on a multiple sequence alignment. Alternatively, the skilled person may compare the antibody sequences to a publicly available database operating on Kabat, Chothia or IMGT methods using the BLASTP command of BLAST+ to identify the most similar annotated sequence. Each of these methods has devised a unique residue numbering scheme according to which it numbers the hypervariable region residues and the beginning and ending of each of the six CDRs is then determined according to certain key positions. Upon alignment with the most similar annotated sequence, for example, the CDRs can be extrapolated from the annotated sequence to the non-annotated sequence, thereby identifying the CDRs. Suitable tools/databases are: the Kabat database, Kabatman, Scalinger, IMGT, Abnum for example.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a variable heavy domain (VH) and variable light domain (VL) pair selected from Table 1.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VH domain of the sequence of SEQ ID NO: 1 and a VL domain of the sequence of SEQ ID NO: 19.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VH domain of the sequence of SEQ ID NO:7 and a VL domain of the sequence of SEQ ID NO:25.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VH domain of the sequence of SEQ ID NO: 11 and a VL domain of the sequence of SEQ ID NO:29.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VH domain of the sequence of SEQ ID NO: 13 and a VL domain of the sequence of SEQ ID NO:31.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VH domain of the sequence of SEQ ID NO: 16 and a VL domain of the sequence of SEQ ID NO:34.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VH domain of the sequence of SEQ ID NO: 17 and a VL domain of the sequence of SEQ ID NO:35.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VH domain of the sequence of SEQ ID NO:46 and a VL domain of the sequence of SEQ ID NO:47.

Suitably, therefore, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises 3 CDRs, for example in a heavy chain variable region independently selected from SEQ ID NO: 1, 7, 11, 13, 16, 17 and 18.

Suitably the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises 3 CDRs in a heavy chain variable region according to SEQ ID NO: 1.

Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises 3 CDRs in a light chain variable region independently selected from SEQ ID NO: 19, 25, 29, 31, 34, 35 and 36. Suitably, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises 3 CDRs in a light chain variable region according to SEQ ID NO: 19.

Suitably, therefore, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises 3 CDRs, for example in a heavy chain variable region independently selected from SEQ ID NO: 1, 7, 11, 13, 16, 17 and 18 and 3 CDRs, for example in a light chain variable region independently selected from SEQ ID NO: 19, 25, 29, 31, 34, 35 and 36.

Suitably, therefore the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises 3 CDRs in a heavy chain variable region according to SEQ ID NO: 1, and 3 CDRs in a light chain variable region according to SEQ ID NO: 19.

Suitably, therefore, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a variable heavy domain (VH) and a variable light domain (VL) having VH CDRs 1-3 having the sequences SEQ ID NO: 37, 38 and 39, respectively, wherein one or more VHCDRs have 3 or fewer single amino acid substitutions, insertions and/or deletions.

Suitably, therefore, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VH domain which comprises VHCDRs 1-3 of SEQ ID NO: 37, SEQ ID NO: 38 and SEQ ID NO: 39, respectively.

Suitably, therefore, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VH domain which comprises VHCDRs 1-3 consisting of SEQ ID NO: 37, SEQ ID NO: 38 and SEQ ID NO: 39, respectively.

Suitably, therefore, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a variable heavy domain (VH) and a variable light domain (VL) having VL CDRs 1-3 having the sequences of SEQ ID NO: 40, 41 and 42, respectively, wherein one or more VLCDRs have 3 or fewer single amino acid substitutions, insertions and/or deletions.

Suitably, therefore, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VL domain which comprises VLCDRs 1-3 of SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, respectively.

Suitably, therefore, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VL domain which comprises VLCDRs 1-3 consisting of SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, respectively.

Suitably, therefore, the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VHCDR1 having the sequence of SEQ ID NO: 37, a VHCDR2 having the sequence of SEQ ID NO: 38, a VHCDR3 having the sequence of SEQ ID NO: 39, a VLCDR1 having the sequence of SEQ ID NO: 40, a VLCDR2 having the sequence of SEQ ID NO: 41, and a VLCDR3 having the sequence of SEQ ID NO: 42.

Suitably, therefore the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VH and VL, wherein the VH has an amino acid sequence at least 90%, for example 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identical to a VH according to SEQ ID NO: 1, 7, 11, 13, 16, 17, 18, and 46.

Suitably, therefore the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VH and VL, wherein the VH has an amino acid sequence at least 90%, for example 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identical to a VH according to SEQ ID NO: 1.

Suitably, therefore the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VH and VL, wherein a VH disclosed above, has a sequence with 1, 2, 3 or 4 amino acids in the framework deleted, inserted and/or independently replaced with a different amino acid.

Suitably, therefore the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VH and VL, wherein the VL has an amino acid sequence at least 90%, for example 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identical to a VL according to SEQ ID NO: 19, 25, 29, 31, 34, 35, 36 and 47.

Suitably, therefore the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VH and VL, wherein the VL has an amino acid sequence at least 90%, for example 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identical to a VL according to SEQ ID NO: 19.

Suitably, therefore the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VH and VL, wherein a VL disclosed above has a sequence with 1, 2, 3 or 4 amino acids in the framework independently deleted, inserted and/or replaced with a different amino acid.

Suitably, therefore the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VH and VL, wherein the VH has an amino acid sequence at least 90%, for example 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identical to a VH according to SEQ ID NO: 1, 7, 11, 13, 16, 17, 18, and 46 and VL has an amino acid sequence at least 90%, for example 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identical to a VL according to SEQ ID NO: 19, 25, 29, 31, 34, 35, 36, and 47.

Suitably, therefore the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VH and VL, wherein the VH has an amino acid sequence consisting of SEQ ID NO: 1, 7, 11, 13, 16, 17, 18, and 46 and the VL has an amino acid sequence consisting of SEQ ID NO: 19, 25, 29, 31, 34, 35, 36, and 47.

Suitably, therefore the anti -IL-33 antibody, binding fragment, or antibody variant thereof comprises a VH and VL, wherein the VH has an amino acid sequence consisting of SEQ ID NO: 1, and the VL has an amino acid sequence consisting of SEQ ID NO: 19. In some instance the anti -IL-33 antibody, binding fragment, or variant thereof useful in the present methods comprises a heavy chain set forth in SEQ ID NO: 43 or a sequence 80, 85, 90 or 95% identical thereto and/or a light chain set forth in SEQ ID NO: 44 or a sequence 80, 85, 90 or 95% identical thereto. In some instances, the heavy chain has the sequence set forth in SEQ ID NO: 43 and the light chain has the sequence set forth in SEQ ID NO: 44. In some instances, the anti -IL-33 antibody, binding fragment, or variant thereof useful in the present methods comprises a heavy chain consisting of the sequence set forth in SEQ ID NO: 43, and a light chain consisting of the sequence set forth in SEQ ID NO: 44.

In some instances, IL-33 signalling axis antagonist is the antibody is 33_640087_7B, as disclosed in WO2016/156440, which is incorporated herein by reference. 33_640087_7B, also referred to in the art as MEDI3506 or tozorakimab. Tozorakimab is a monoclonal antibody that binds to IL-33 and potently and specifically blocks all forms of IL-33 to prevent their signalling. Tozorakimab is an example of an IL-33 signalling axis antagonist. Tozorakimab also inhibits the conversion of redIL-33 to the oxidised form (oxIL-33).

Tozorakimab is an exemplary anti -IL-33 antibody having : (a) a heavy chain variable region comprising a VHCDR1 having the sequence as set forth in SEQ ID NO: 37, a VHCDR2 having the sequence of SEQ ID NO: 38, a VHCDR3 having the sequence of SEQ ID NO: 39; and (b) a light chain variable region a VLCDR1 having the sequence of SEQ ID NO: 40, a VLCDR2 having the sequence of SEQ ID NO: 41, and a VLCDR3 having the sequence of SEQ ID NO: 42.

Tozorakimab also comprises a VH domain having the amino acid sequence as set forth in SEQ ID NO: 1 and a VL domain having the amino acid sequence as set forth in SEQ ID NO: 19.

Tozorakimab is an IgGl antibody, the sequence of the full length heavy and light chain of tozorakimab, including the IgGl chain, is set forth in SEQ ID NOs: 43 and 44, respectively.

In some instances, therefore, the antibody is tozorakimab, or a binding fragment or variant thereof. Suitably therefore in some instances, the IL-33 signalling axis antagonist is tozorakimab, or a binding fragment or variant thereof. Suitably therefore in some instances, the IL-33 signalling axis antagonist is tozorakimab.

In some instances, the IL-33 signalling axis antagonist is an anti -IL-33 antibody, binding fragment, or antibody variant thereof that has similar, or the same, pharmacokinetic (pK) characteristics as tozorakimab in humans.

In particular, an anti -IL-33 antibody, binding fragment, or antibody variant for use in the present methods may have a similar, or the same, half-life in humans as tozorakimab. The anti -IL-33 antibody, binding fragment, or antibody variant having a similar, or the same, half-life in humans as tozorakimab, when administered at a dose of 30 mg Q2W, may have a half-life of about 10 to about 20 days, about 12 to about 15 days, or of about 12.7 days. The anti -IL-33 antibody, binding fragment, or antibody variant having a similar, or the same, half-life in humans as tozorakimab, when administered at a dose of 100 mg Q2W, may have a half-life of about 10 to about 20 days, about 12 to about 15 days, or of about 13.2 days. The anti-IL-33 antibody, binding fragment, or antibody variant having a similar, or the same, half-life in humans as tozorakimab, when administered at a dose of 300 mg Q2W, may have a half-life of about 10 to about 20 days, about 12 to about 15 days, or of about 14.8 days.

In some instances, the IL-33 antibody, binding fragment, or variant thereof may competitively inhibit binding of IL-33 to tozorakimab (as described in WO2016/156440). WO2016/156440 discloses that tozorakimab binds to redIL-33 with particularly high affinity. An antibody, binding fragment, or variant thereof is said to competitively inhibit binding of a reference antibody to a given epitope if it specifically binds to that epitope to the extent that it blocks, to some degree, binding of the reference antibody to the epitope. Competitive inhibition may be determined by any method known in the art, for example, solid phase assays such as competition ELISA assays, Dissociation-Enhanced Lanthanide Fluorescent Immunoassays (DELFIA®, Perkin Elmer), and radioligand binding assays. For example, the skilled person could determine whether an antibody, binding fragment, or variant thereof competes for binding to IL-33 by using an in vitro competitive binding assay, such as the HTRF assay described in WO2016/156440, paragraphs 881-886, which is incorporated herein by reference. For example, the skilled person could label tozorakimab with a donor fluorophore and mix multiple concentrations with fixed concentration samples of acceptor fluorophore labelled-redIL-33. Subsequently, the fluorescence resonance energy transfer between the donor and acceptor fluorophore within each sample can be measured to ascertain binding characteristics. To elucidate competitive binding antibody molecules, the skilled person could first mix various concentrations of a test binding molecule with a fixed concentration of the labelled tozorakimab antibody. A reduction in the FRET signal when the mixture is incubated with labelled IL-33 in comparison with a labelled antibody -only positive control would indicate competitive binding to IL-33. An antibody, binding fragment, or variant thereof may be said to competitively inhibit binding of the reference antibody to a given epitope by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

Pharmaceutical composition

In some instances, the effective amount of the tozorakimab or the IL-33 signaling axis antagonist is comprised in a pharmaceutical composition, comprising one or more excipients. Suitably, the tozorakimab or the IL-33 signaling axis antagonist is administered to the subject in the form of a pharmaceutical composition.

Suitably, any references herein to ‘a/the tozorakimab or a/the IL-33 signaling axis antagonist’ may also refer to a pharmaceutical composition comprising an/the tozorakimab or a/the IL-33 signaling axis antagonist. Suitably the pharmaceutical composition may comprise one or more IL-33 signaling axis antagonists.

The pharmaceutical compositions may be formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, and the like. A multitude of formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. Thus, the pharmaceutical compositions may comprise, in addition to the active ingredient (i.e. the anti -IL-33 antibody), a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other material well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration, which may be by injection, e.g. intravenous or subcutaneous.

For subcutaneous injection, the pharmaceutical composition may be an aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.

The pharmaceutical composition may be a liquid formulation provided in the form of containers with defined volume, including sealed and sterilized plastic or glass vials, ampoules and syringes, as well as in the form of large volume containers like bottles. Suitably, in the methods described herein, the pharmaceutical composition is a liquid formulation.

Suitably, the anti -IL-33 antibody, may be present within the pharmaceutical composition at a concentration of from 100 mg/ml to 200 mg/ml, more suitably 150 mg/ml. In particular, when an antibody dose of 300 mg is used, the antibody (particularly tozorakimab) may be provided in 2 ml of a 150 mg/ml liquid composition.

Suitably, the anti-IL-33 antibody may be buffered to a pH of 5.2 to 5.7, most suitably 5.5 (e.g. ± 0.1). The selection of such a pH confers significant stability to the pharmaceutical composition.

It will be appreciated that references to a "pharmaceutically acceptable excipient" includes references to any excipient conventionally used in pharmaceutical compositions. Such excipients may typically include one or more surfactant, inorganic or organic salt, stabilizer, diluent, solubilizer, reducing agent, antioxidant, chelating agent, preservative and the like.

Suitably, the surfactant is present within the pharmaceutical composition in an amount of from 0.001% to 0.1% (w/w). Suitably, the surfactant is polysorbate-80 (PS-80).

The anti -IL-33 antibody (particularly tozorakimab) may be provided in a pharmaceutical composition comprising L-histidine and/or L-histidine hydrochloride, L-arginine hydrochloride and polysorbate 80. The composition may in particular comprise 20 mM ± 10 % L-histidine/L-histidine hydrochloride, e.g. 20 mM ± 2.5 %, 5 % or 7.5 % L-histidine/L-histidine hydrochloride. That is to say L-histidine/L- histidine hydrochloride may be present in the composition at a concentration from 18-22, 18.5-21.5, 19-21 or 19.5-20.5 mM, suitably at a concentration of 20 mM.

The composition may in particular comprise 220 mM ± 10 % L-arginine hydrochloride, e.g. 220 mM ± 2.5 %, 5 % or 7.5 % L-arginine hydrochloride. For instance, L arginine hydrochloride may be present in the composition at a concentration from 200 240, 205-235, 210-230 or 215-225 mM, suitably at a concentration of 220 mM.

The composition may in particular comprise 0.03 % w/v ± 10 % polysorbate 80, e.g. 0.03 % w/v ± 2.5 %, 5 % or 7.5 % polysorbate 80. For instance, polysorbate 80 may be present in the composition at a concentration from 0.027-0.033, 0.028-0.032 or 0.029-0.031 % w/v, suitably at a concentration of 0.03 % w/v.

The composition may have a pH from 5.2-5.7, 5.3-5.6 or 5.4-5.5, suitably 5.5.

In a particular instance the pharmaceutical composition comprises 20 mM L histidine/L-histidine hydrochloride, 220 mM L-arginine hydrochloride and 0.03 % polysorbate 80, and has a pH of 5.5. Suitably the pharmaceutical composition also comprises 150 mg/ml tozorakimab. When the composition comprises 150 mg/ml tozorakimab, a 300 mg dose of the antibody can be administered in 2 ml of the composition.

Administration Regimens

The present disclosure also relates to dosage regimens of an IL-33 signalling axis antagonist, which finds particular effectiveness in the treatment of COPD.

A dosage regimen is made up of one or more doses of a controlled size, administered throughout a treatment window. Where there is more than one dose, the doses are separated by a dosing interval. The IL-33 signalling axis antagonist is administered in a therapeutically effective amount. As defined hereinabove, an “effective amount” or “therapeutically effective amount” of an agent, e.g., a pharmaceutical formulation comprising an IL-33 antibody, refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.

In some instances, therefore, the IL-33 signalling axis antagonist or pharmaceutical composition thereof is administered at a dose that achieves at least 80%, 85% or 90% target engagement in the lung. In some instances, the dose achieves at least 90% target engagement in the lung. In some instances, the dose achieves at least 91%, 92%, 93% or 94% target engagement in the lung. In some instances the % target engagement is achieved at trough concentration.

Methods of administering the IL-33 signalling axis antagonist or a pharmaceutical composition thereof to a subject in need thereof are well known to or are readily determined by those skilled in the art, and are described hereinbelow. The size of the dose of IL-33 signalling axis antagonist may be expressed in terms of weight of the IL-33 signalling axis antagonist . In certain instances, the IL-33 signalling axis antagonist is administered in a dose of about 400 to about 800 mg, about 450 to about 750 mg, about 500 to about 700 mg, about 510 to about 690 mg, about 520 to about 680 mg, about 530 to about 670 mg, about 540 to about 660 mg, about 550 to about 650 mg, about 560 to about 640 mg, about 570 to about 630 mg, about 580 to about 620 mg, about 590 to about 630 mg, or about 600 mg. In some instances, the dose is 600 mg. In some instances, the IL-33 signalling axis antagonist is formulated for subcutaneous injection at 150 mg/mL, such that a 600 mg dose is administered as a 4 mL treatment. A 600 mg dose of the IL-33 signalling axis antagonist may be administered as two concurrent 300 mg dosages. As used herein, “concurrent” doses refer to doses which are administered simultaneously, or sequentially with no or only a minimal time period (e.g. less than 1 hour, less than 30 minutes, less than 15 minutes, less than 5 minutes) separating them.

In some instances, the IL-33 signalling axis antagonist is administered in a dose of about 200 to about 400 mg, about 250 to about 350 mg, about 260 to about 340 mg, about 270 to about 330 mg, about 280 to about 320 mg, about 290 to about 310 mg, about 295 to about 305 mg or about 300 mg.

In some instances, the dose is 300 mg. In some instances, the IL-33 signalling axis antagonist is formulated for subcutaneous injection at 150 mg/mL, such that a 300 mg dose is administered as a 2 mL treatment. In some instances, a 300 mg dose of the IL-33 signalling axis antagonist may be administered as two concurrent 150 mg dosages. As used herein, “concurrent” doses refer to doses which are administered simultaneously, or sequentially with no or only a minimal time period (e.g. less than 1 hour, less than 30 minutes, less than 15 minutes, less than 5 minutes) separating them.

In some instances, the dose is 150 mg. In some instances, the IL-33 signalling axis antagonist is formulated for subcutaneous injection at 150 mg/mL, such that a 150 mg dose is administered as a 1 mL treatment.

The size of the dose of an IL-33 signalling axis antagonist may be expressed in terms of the plasma drug concentration provided by the dose, as the amount of active compound manipulated so as to provide a plasma drug concentration of a certain level. By varying the amount, bioavailability, or timing/frequency of the antibody or variant administered, the skilled person can control the plasma concentration in the subject. As plasma concentrations vary across time with drug uptake and clearance, they may be expressed in various standardised ways - for example as a maximum, minimum (trough) or across time.

In some instances, the dose is selected so as to provide a C_maX;SS (the observed maximum concentration at steady state) of between about 20 and about 50 pg/mL, between about 25 and about 45 pg/mL, between about 30 and about 40 pg/mL, between about 35 and about 40 pg/mL, or about 37 pg/mL In some instances, the C_{maz ss} is that observed during the dosing period. In this context, the “dosing period” refers to the time between two consecutive doses. The IL-33 signalling axis antagonist serum concentration can be measured (and therefore used to determine C_{max ss}) anti-drug antibody reagents in a suitable assay format to capture and detect IL-33 signalling axis antagonist from a biological sample (e.g. blood). In some instances, the assay may use an anti-IgGl capture mAb and a stabilised tozorakimab (for example) antigen labelled with a detectable marker. The detectable marker can be quantified in order to determine the concentration of tozorakimab. In some instances, the tozorakimab antigen (IL-33) may be stabilised in a reduced form, for example, by mutating one or more cysteine residues to serine. Assays and platforms suitable for the detection of serum biomarkers are well known to the skilled person.

In some instances, the dose is selected so as to provide a C_maX;SS of between about 10 and about 35 pg/mL, between about 15 and about 30 pg/mL, between about 15 and about 30 pg/mL, between about 15 and about 25 pg/mL, about 15 to about 20 pg/mL, or about 18.6 pg/mL.

In some instances, the IL-33 signalling axis antagonist is administered in a dose selected so as to provide an area under the plasma concentration-time curve throughout a dosing period (AUC).

In some instances, the dose is selected so as to provide an AUC of between about 400 and about 800 pg • day/mL, between about 500 and about 750 pg • day/mL, between about 600 and about 700 pg • day/mL, between about 600 and about 650 pg • day/mL, between about 600 and about 620 pg • day/mL, between about 610 and about 620 pg • day/mL, or about 616 pg • day/mL over the dosing period.

In some instances, the dose is selected so as to provide an AUC of between about 200 and about 515 pg • day/mL, between about 250 and about 500 pg • day/mL, between about 300 and about 450 pg • day/mL, between about 300 and about 350 pg • day/mL, or about 323 pg • day/mL over the dosing period.

In some instances, the dose is selected so as to provide an AUC of between about 100 and about 300 pg • day/mL, between about 100 and about 250 pg • day/mL, between about 100 and about 200 pg • day/mL, between about 150 and about 200 pg • day/mL, or about 161.5 pg • day/mL over the dosing period.

Administration of the IL-33 signalling axis antagonist is performed as multiple doses separated by a dosing interval. In some instances, the dosing interval is 2 weeks (14 days), 3 weeks (21 days), 4 weeks (28 days) or 5 weeks (35 days). In some instances, the dosing interval is 4 weeks (28 days). In some instances, the dosing interval is about 2 weeks (i.e. 14 ± 4 days). In some instances, the dosing interval is about 4 weeks (i.e. 28 ± 4 days). In some instances, the dosing interval is about 8 weeks (i.e. 56± 4 days).

In some instances, a dose may be administered across multiple days, for example, as two or more subdoses. As used herein, a “sub-dose” is a fractional quantity of a dose of therapeutic, such that the total quantity of therapeutic administered in sub-doses is equal to that in the dose. Any fractional quantity may be used, for example such that two, three, four, five or more sub-doses comprise a single dose. In some instances, a dose may be administered as two or more sub-doses separated by a period of 1, 2, 3, 4, 5, or 6 days. In some instances, a dose may be administered as two or more sub-doses separated by a period of 1, 2, or 3 weeks. Sub-doses may be administered on two, three, four or more consecutive days. Sub-doses which make up a dose may be of equal size, or may differ in size, so long as their total is equal to the dose.

Therefore, as used herein, a dose of 600 mg with a 4 week dosing window (Q4W) may be substituted for 150 mg administered weekly (Q1W), 300 mg administered every 2 weeks (Q2W), or 450 mg administered every 3 weeks (Q3W), all of which provide a dosing regimen equivalent to 600 mg every 4 weeks. Thus, in some instances, the dose is about 300 mg Q2W. A dose of 300 mg with a 4 week dosing window (Q4W) may be substituted for 150 mg administered every two weeks (Q2W) or 75 mg administered weekly(QlW). A dose of 300 mg with an 8 week dosing window (Q8W) may be substituted for 150 mg administered every four weeks (Q4W) or 75 mg administered every two weeks (Q2W), or 37.5 mg administered every week (Q1W).

In some instances, the IL-33 signalling axis antagonist or pharmaceutical composition thereof is administered to the subject every 2 weeks (Q2W), 4 weeks (Q4W), five weeks (Q5W), 6 weeks (Q6W), seven weeks (Q7W), or 8 weeks (Q8W).

In some instances, the IL-33 signalling axis antagonist or pharmaceutical composition thereof is administered at about 300 mg Q2W. In some instances, the IL-33 signalling axis antagonist or pharmaceutical composition thereof is administered at about 600 mg Q4W. In some instances, the IL- 33 signalling axis antagonist or pharmaceutical composition thereof is administered at about 300 mg Q4W. In some instances, the IL-33 signalling axis antagonist or pharmaceutical composition thereof is administered at about 300 mg Q8W.

In some instances, the effective amount of the IL-33 signalling axis antagonist is a dose of between 300mg to 600mg. The effective amount of an IL-33 signalling axis antagonist may be a dose of between 300mg to 600mg of tozorakimab.

In some instances, the IL-33 signalling axis antagonist or pharmaceutical composition thereof is administered to the subject at a dose of 600 mg every 4 weeks (Q4W). In some instances, tozorakimab or a pharmaceutical composition thereof is administered to the subject at a dose of 600 mg every 4 weeks (Q4W). In some instances, the IL-33 signalling axis antagonist or pharmaceutical composition thereof is administered to the subject at a dose of 300 mg every 2 weeks (Q2W). In some instances, tozorakimab or pharmaceutical composition thereof is administered to the subject at a dose of 300 mg every 2 weeks (Q2W). In some instances, the IL-33 signalling axis antagonist or pharmaceutical composition thereof is administered to the subject at a dose of 300 mg every 4 weeks (Q4W). In some instances, tozorakimab or pharmaceutical composition thereof is administered to the subject at a dose of 300 mg every 4 weeks (Q4W). In some instances, the IL-33 signalling axis antagonist or pharmaceutical composition thereof is administered to the subject at a dose of 300 mg every 8 weeks (Q8W). In some instances, tozorakimab or pharmaceutical composition thereof is administered to the subject at a dose of 300 mg every 8 weeks (Q8W).

When the dosing interval is expressed as a number of weeks, a margin of error is permissible such that a week may be expressed as 7 days ± 1 day. In some instances, a week may be expressed as 7 days ± 0.5 days, 7 days ± 0.25 days, or exactly 7 days. Where the dosing interval is multiple weeks, the margins of error in each week may be combined. For example, in some instances, the dosing interval is 4 weeks ± 4 days. In some instances, the dosing interval is 4 weeks ± 3 days. In some instances, the dosing interval is 4 weeks ± 2 days. In some instances, the dosing interval is 4 weeks ± 1 day. In some instances, the dosing interval is exactly 4 weeks. In some instances, the dosing interval is 8 weeks ± 4 days. In some instances, the dosing interval is 8 weeks ± 3 days. In some instances, the dosing interval is 8 weeks ± 2 days. In some instances, the dosing interval is 8 weeks ± 1 day. In some instances, the dosing interval is exactly 8 weeks.

In some instances, the IL-33 signalling axis antagonist or pharmaceutical composition thereof is administered during a “treatment window”, which as used herein refers to a period commencing at the administration of the first dose and running until the final dose of the anti -IL-33 antibody or antibody variant thereof is administered. The date the first dose is administered is referred to as “Day 1” of “Week 0”, with Week 1 commencing 7 days later, Week 2 commencing 7 days after that, and so on. In some instances, the treatment window is 12 weeks long (i.e. running from Week 0 to Week 12). In some instances, the treatment window is 16 weeks long (i.e. running from Week 0 to Week 15) and the dosing interval is 4 weeks, such that a total of 4 doses are administered (on Week 0, 4, 8 and 12 respectively). In some instances, the treatment window is 12 weeks long, and the dosing interval is 4 weeks, such that doses are administered Days 1 (Week 0), 29 ± 4 (Week 4), 57 ± 4 (Week 8), and 85 ± 4 (Week 12).

In some instances, the treatment window is 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, 42 weeks, 44 weeks, 46 weeks, 48 weeks, 50 weeks, 52 weeks or more. In some instances, the treatment window is 52 weeks or more. In some instances, the treatment window is 48 weeks or more. In one instance, the treatment window is 24 weeks. In one instance, the treatment window is 24 weeks long, and the dosing interval is 4 weeks. In some instances, the IL-33 signalling axis antagonist or pharmaceutical composition thereof is administered to the subject subcutaneously. In some instances, the IL-33 signalling axis antagonist or pharmaceutical composition thereof is administered to the subject by injection. In some instances, the IL-33 signalling axis antagonist or pharmaceutical composition thereof is administered to the subject by subcutaneous injection.

In some instances, particularly wherein the IL-33 signalling axis antagonist is an anti -IL-33 antibody (such as tozorakimab), the antibody may be provided in a pharmaceutical composition comprising L- histidine and/or L-histidine hydrochloride, L-arginine hydrochloride and polysorbate 80. The composition may in particular comprise 20 mM ± 10 % L-histidine/L-histidine hydrochloride, e.g. 20 mM ± 2.5 %, 5 % or 7.5 % L-histidine/L-histidine hydrochloride. That is to say L-histidine/L-histidine hydrochloride may be present in the composition at a concentration from 18-22, 18.5-21.5, 19-21 or 19.5-20.5 mM, suitably at a concentration of 20 mM.

In some instances, the composition comprises 220 mM ± 10 % L-arginine hydrochloride, e.g. 220 mM ± 2.5 %, 5 % or 7.5 % L-arginine hydrochloride. For instance, L arginine hydrochloride may be present in the composition at a concentration from 200 240, 205-235, 210-230 or 215-225 mM, suitably at a concentration of 220 mM.

In some instances, the composition comprises 0.03 % w/v ± 10 % polysorbate 80, e.g. 0.03 % w/v ± 2.5 %, 5 % or 7.5 % polysorbate 80. For instance, polysorbate 80 may be present in the composition at a concentration from 0.027-0.033, 0.028-0.032 or 0.029-0.031 % w/v, suitably at a concentration of 0.03 % w/v.

In some instances, the composition may have a pH from 5.2-5.7, 5.3-5.6 or 5.4-5.5, suitably 5.5.

In one instance, the pharmaceutical composition comprises 20 mM L histidine/L-histidine hydrochloride, 220 mM L-arginine hydrochloride and 0.03 % polysorbate 80, and has a pH of 5.5. Suitably the pharmaceutical composition also comprises 150 mg/ml tozorakimab.

The following aspects are not claims but are numbered instances which may be useful in the present disclosure:

EXAMPLES

Example 1 - A Phase II, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Safety and Tolerability of MEDI3506 in Participants with Moderate to Severe Chronic Obstructive Pulmonary Disease and Chronic Bronchitis (FRONTIER 4)

The present example describes a Phase 2 randomized, double-blinded, placebo-controlled, parallel- group, proof-of-concept study to evaluate the efficacy, safety, PK, and immunogenicity of MEDI3506 (tozorakimab) in adult subjects with moderate or severe COPD receiving Standard of Care (dual or triple therapy) as maintenance therapy. Participants also have ahistory of > 1 moderate or severe acute exacerbation in the previous 12 months while on stable background treatment, and moderate to severe chronic bronchitis, with active sputum and cough symptoms. The intervention period lasts 28 weeks (7 doses).

Tozorakimab (also referred to herein as 33 640087 7B) is a human IgGl mAb that binds to human IL-33. Tozorakimab binds full length and mature forms of human IL-33 with exceptionally high affinity and prevents IL-33 binding to soluble (sST2) and membrane-bound forms of ST2 (also known as IL-1RL1) receptor.

Several clinical and non-clinical studies point to the IL-33/ST2 signalling axis playing a key role in the pathogenesis of COPD. Thus, blocking this signalling pathway could be of therapeutic benefit in COPD.

Participants must be on stable doses of dual therapy (ICS + LABA, or LABA + LAMA) or triple therapy (ICS + LABA + LAMA) for > 3 months prior to enrolment and should remain so during the study. There should have been no change in maintenance COPD treatment after a previous exacerbation prior to entering into the study.

Approximately 140 participants will be randomised into treatment groups which will receive 600 mg tozorakimab SC (20 mM L-histidine/L-histidine-hydrochloride, 220 mM L-arginine-hydrochloride, 0.03% (w/v) polysorbate 80, pH 5.5), or volume -matched placebo SC (referred to collectively “investigational products” or “IP”); in a 1 : 1 ratio overall every 4 weeks (Q4W) for a total of 7 doses with the final dose at Week 24.

Participants will be enrolled in this study for at least a 4-week screening/run-in period, a 24-week intervention period (or “treatment window”) during which they receive 7 doses SC Q4W, a 4 week additional period, and an 8-week follow-up period.

The primary estimand is as follows: The difference in mean change from baseline in pre-BD FEVi at Week 12 (tozorakimab - placebo) will be estimated using a repeated measures mixed effects analysis of covariance model, for the ITT (Intent to treat) population. This will include all available data from all visits up to and including Week 12, irrespective of whether the participant discontinued study intervention or received reliever therapy. The model will include fixed effects for baseline, eosinophil strata, background medication strata, visit, study intervention, and the baseline by visit, and study intervention by visit interactions. An unstructured covariance matrix will be used to describe the correlations between observations on a participant between visits.

The primary endpoint, together with key secondary or exploratory endpoints are described in Table 2 below: Table 2: Study endpoints

AE = Adverse event; AECOPD = Acute exacerbation of chronic obstructive pulmonary disease; AO = Airwave oscillometry; BOSS = Breathlessness, cough and sputum scale; BD = Bronchodilator; CASA-Q = Cough and sputum assessment questionnaire; COPD = Chronic obstmctive pulmonary disease; COPDCompEx = COPD Composite Exacerbations; E-RS:COPD = Evaluating Respiratory Symptoms of COPD; FEVi = Forced expiratory volume 1 second; FVC = Forced vital capacity; IL = Interleukin; SGRQ = St. George’s Respiratory Questionnaire; sST2 = Soluble suppression of tumorgenicity 2; ST2 = Suppression of tumorgenicity 2;.

Study Population

Each participant should meet all the inclusion criteria in order to be assigned/randomized to the study intervention:

Inclusion Criteria

1. Participants must be 40 to 75 years of age inclusive. 2. Participants who are current or ex-smokers with a tobacco history of > 10 pack -years. Pack- years are calculated as average number of cigarettes per day x number of years / 20

3. Participants who are up-to-date on pneumococcus and influenza vaccines as per local treatment guidelines.

4. Participants who have a documented history of COPD for at least 1 year.

5. Participants who have a post-BD FEVi/FVC < 0.70 and a post-BD FEVi > 30% and < 80% predicted normal value at screening. Centralized spirometry will be used for this criteria assessment.

6. Participants who have a physician confirmed participant history of chronic bronchitis as defined as presence of cough and sputum on most days for > 3 mos/yr in at least the 2 year period immediately prior to screening.

7. Participants who have an average BCSS score of > 2 in cough and > 2 in sputum domains assessed over the 14 days preceding subject visit (SV) 3.

8. Participants who have a documented stable regimen of dual therapy or triple therapy for > 3 months prior to enrolment; there should have been no change in treatment after the previous exacerbation prior to entering into the study. Where dual therapy consists of ICS + LABA or LABA + LAMA, and triple therapy consists of ICS + LABA + LAMA. Both dual and triple therapy may be in the form of separate inhalers of fixed dose combination inhalers but may not be in nebulized form.

9. Participants who have a documented history of > 1 moderate or severe AECOPD requiring systemic corticosteroids and/or antibiotics for at least 3 days duration (or 1 injection of depot formulation), or hospitalization for reason of AECOPD in the previous 12 months prior to screening.

10. Participants who are clinically stable and free from an exacerbation of COPD for 1 month prior to screening and prior to Day 1.

11. Body mass index within the range 19 to 35 kg/m² (inclusive).

Randomisation and Administration

A sample size of 140 participants (70 participants per arm) will provide 80% power to detect a difference in mean change from baseline in FEVi at Week 12 of 90 mL (assumed SD of 250 mL) between the 2 randomized groups at a one-sided 10% level of statistical significance. To allow for 2% of participants being ineligible for the primary analysis, approximately 144 Participants will be randomized in the study (72 per arm). Randomisation will occur at study visit 3 (SV3 - Day 1). Participants who continue to meet eligibility criteria will be randomised into treatment groups as described above. Blood samples, urine samples, efficacy assessments and safety assessments will be performed in order to establish baseline. In general, the last measurement prior to first injection of IP will serve as the baseline measurement for efficacy and safety endpoints. Absolute and percent change from baseline will be derived as follows: Absolute change from baseline outcome variables = (post-randomization value - baseline value). Percent change from baseline = ((post-randomization value - baseline value) / baseline value) x 100. For any variable subjected to log transformation, the change from baseline calculated and summarised on the log scale will be back transformed and presented as a ‘baseline scaled ratio’ (BSR). Percentage change will then be calculated as (BSR - 1) x 100.

The randomization will be stratified by baseline blood eosinophils (< 300 cells/pL vs > 300 cells/pL) and background medication (includes ICS vs does not include ICS).

The first investigational product (IP) administration will occur at study visit 3 (Day 1), and will comprise administering the first dose of investigational product during the treatment window. Administering 600 mg MEDI3506 will require 2 x 2 mL SC injections per dose. Placebo groups will be injection volume matched to the MEDI3506 groups.

At study visit 4 (Day 2), participants will return for assessment of their adherence to self-assessment efficacy reporting procedures, and safety assessments.

The second investigational product administration will occur at study visit 6 (Day 29 ± 3).

The third investigational product administration will occur at study visit 7 (Day 57 ± 3).

The fourth investigational product administration will occur at study visit 8 (Day 85 ± 3).

The fifth investigational product administration will occur at study visit 9 (Day 113 ± 3).

The sixth investigational product administration will occur at study visit 10 (Day 141 ± 3).

The seventh and final investigational product administration will occur at study visit 11 (Day 169 ± 3).

Whenever data is summarised over time, study day will be calculated based on the actual assessment date. All data will be summarised in relation to date of first IP administration.

Endpoints

The primary endpoint visit occurs at week 12, as assessed at study visit 10 (day 113 ± 4).

The primary endpoint is improvement is change from baseline to week 12 in clinic pre-BD FEVi. Forced expiratory volume in 1 second is a validated and clinically important endpoint in COPD studies, and has been used extensively in trials used to support registration of add on therapy to current standard of care (dual/triple therapy) in a similar chronic bronchitis patient population (Martinez et al 2015).

Based on available data, the improvement in FEVi assumed in the sample size determination is expected to be achieved by Week 12. However, improvement in FEVi is considered important but not sufficient to meet the unmet medical need in COPD. To enable evaluation of the secondary endpoint of COPDCompEx, the treatment is continued after collection of primary endpoint data, to collect further events. The longer intervention period duration also allows the exploratory assessment of treatment effect on FEVi beyond Week 12.

The secondary endpoint is COPDCompEx at week 28. Changes in clinic pre-BD FEVi will also be assessed at week 28.

Analysis for the secondary endpoints (change from baseline through Week 28 in pre-BD and post-BD FEVi, pre-BD and post BD FVC) by extent of emphysema (< 10% vs > 10%) will be performed.

Analysis for the exploratory endpoints (time to first COPDCompEx event based on the period from baseline to Week 28, change from baseline in BCSS cough and sputum scores throughWeek 28) by extent of emphysema (< 10% vs > 10%) will be performed.

Subgroup analysis will also be performed for: Baseline blood eosinophils count (< 150cells/pL vs > 150 cells/pL), Smoking status at baseline (current smoker vs former smoker), Baseline BCSS based on 14-day average (<median vs >median), Baseline total SGRQ score (<median vs >median), Extent of emphysema (< 10% vs > 10%).

Change from baseline in pre-BD FEVi measured in clinic at Week 12 is the primary endpoint of the study. Change from baseline in pre-BD FVC measured in clinic and FEVi/FVC ratio are exploratory endpoints of the study. Lung function (FEVi and FVC) will be measured by spirometry using standard equipment. FEVi/FVC ratio will be determined by spirometry device.

Change from baseline in 4-weekly mean pre-BD FEVi measured using home spirometry is an exploratory endpoint of the study. In addition, change from baseline in 4-weekly mean PEF measured at home will be analysed. During the intervention period, participants will be required to monitor lung function at home using an at-home spirometry device for daily recording of FEVi and PEF. Fourweekly mean pre-BD FEVi and PEF will be calculated as average from values collected during the assessment period.

The COPDCompEx is a composite endpoint for exacerbations in COPD. The COPDCompEx combines exacerbations with events defined from participant e-Diaries and PEF, as defined in the relevant section hereinabove. The fulfilment of objective deterioration criteria will be calculated for each (single) diary variable for thresholds and slopes as explained in the relevant section hereinabove. Time to first COPDCompEx event is the secondary endpoint of the study. Time to the first COPD exacerbation on study will be calculated as start date of first COPD exacerbation minus date of first IP administration plus one: [Start date of first event or censoring - date of the first dose of study intervention+ 1], Date of first event will be the first start date of a COPDCompEx event as defined above. For participants who do not experience an on-treatment COPDCompEx event, date of censoring will be the minimum of date of last dose plus 28 days, or last day of eDiary recording if sooner.

The time during the event and the 7 days after each event will not be considered when defining time at risk for the COPDCompEx event rate.

Time to first moderate or severe AECOPD, annualised rate of moderate or severe COPD exacerbations and proportion of participants with > 1 COPD exacerbation at Weeks 12 and 28 are exploratory endpoints for this study. An AECOPD will be defined as a change in the participant’s usual COPD symptoms that lasts 2 or more days, is beyond normal day-to-day variation, is acute in onset, and may warrant a change in regular medication. The change in symptoms must include at least one major COPD symptom and at least one other major or minor symptom from the list below: • Major COPD symptoms: dyspnoea, sputum volume, and sputum colour, Minor COPD symptoms: cough, wheeze, sore throat, cold symptoms (rhinorrhoea or nasal congestion), chest tightness and fever without other cause. An AECOPD will be considered severe if it results in: • An inpatient COPD-related hospitalization; or • COPD-related death.

Time to first moderate or severe AECOPD based on the period during the intervention from baseline through to 4 weeks after the last dose (Week 28) and through to the end of the follow-up period (Week 36) will be calculated. The time to first moderate or severe AECOPD for participants who do not experience a moderate or severe AECOPD during the study will be censored at the date of the last visit for the intervention period (for Week 28 analysis) or date of the last follow-up visit (for Week 36 analysis) or date of early discontinuation from the study (for participants who discontinued prior to Week 28 or Week 36).

Change from baseline to Week 12 in the average BCSS© score over the previous 4 weeks is a secondary endpoint of this study. The BCSS© is a 3 -item daily diary that assesses the severity of the 3 symptoms: breathlessness, sputum, and cough, each on a 5 -point scale as is known in the art. Item scores will be reported as domains scores and are summed to yield a total score. Higher scores for each domain, and thus for total score, indicate more severe symptoms. The BCSS will be captured each evening via the eDiary. The 4-weekly mean BCSS score will be calculated as the sum of all nonmissing daily scores over the 28-day evaluation period, divided by the number of non-missing daily scores. The 4-weekly mean will be calculated if there are at least 14 completed days during the 28-day evaluation period, where a day = evening + following morning. The SGRQ is a 50-item PRO instrument developed to measure the health status of patients with airway obstruction diseases (Jones et al 1991). The SGRQ yields a total score and three domain scores (symptoms, activity, and impacts). The total score indicates the impact of disease on overall health status. This total score is expressed as a percentage of overall impairment, in which 100 represents the worst possible health status and 0 indicates the best possible health status. Likewise, the domain scores range from 0 to 100, with higher scores indicative of greater impairment. Specific details on the scoring algorithms are provided by the developer in a user manual (Jones and Forde 2009). The SGRQ will be completed using the eDiary, and a 4-week recall version will be used. The key outcome variable for the SGRQ will be the change in total SGRQ score from baseline to Week 12, but the change in total score from baseline to Week 4 and Week 28 will also be derived. Change in the domain score from baseline to Week 4, Week 12 and Week 28 will also be derived.

Extent of emphysema on baseline and week 28 chest CT scan will be assessed and categorised as follows:

<5% emphysema (visual score = 1)

>5% to <10% emphysema (visual score = 2)

>10% to <20% emphysema (visual score = 3)

>20% emphysema (visual score = 4)

Blood samples will be collected from subjects for the assessment of biomarkers that are relevant to disease pathology and/or the mechanism of action of MEDI3506. Blood eosinophils count will be collected as part of laboratory assessment, whole blood samples will be collected concurrently for both haematology and assessment of eosinophils. The number of eosinophils is determined per 100 cells by microscopy.

Results

Although there was no statistically significant improvement in clinic pre-BD FEVi at Week 12 for the tozorakimab 600 mg group compared with the placebo group, a numerical improvement of 24 mL was observed (Table 3 and Figure 1). A summary of clinic pre-BD FEVi (L) from baseline to Week 12 is presented in Table 4. Table 3 Change from Baseline to Week 12 in Pre-BD FEVi (L) (As Measured in the Clinic) Treatment Comparisons (ITT Population)*

An unstructured covariance matrix was used to describe the correlations between observations on a subj ect between visits, and Ken ward-Roger correction was used for degrees of freedom approximation in the generation of model. The significance of the treatment effect was tested at a 10% one-sided level of significance.

Table 4 Summary of Clinic Pre-BD FEVi (L) from Baseline to Week 12 (ITT Population) The additional MMRM analysis of the primary endpoint using data from visits up to and including Week 36 was generally consistent with the primary analysis. A nominally significant difference for the tozorakimab 600 mg group compared with placebo was observed at Week 24 (LSMean difference 0.044 L [80% CI: 0.003, 0.086] p = 0.086) and Week 32 (LSMean difference 0.055 L [80% CI: 0.012, 0.098] p = 0.051) only.

From Figure 1, a clear separation of the lines can be seen from Week 2 which was maintained throughout the treatment period and also including follow-up.

Figure 2 shows the change from baseline to Week 12 in pre-BD FEVi measured in the clinic using LSMeans by subgroups. Compared with placebo, participants receiving tozorakimab 600 mg had greater numerical improvement in clinic pre BD FEV i at Week 12 for higher BCSS (85 mL) or SGRQ scores (77 mL), ICS use (56 mL), baseline eosinophils > 150 cells/pL (82 mL) or > 2 prior COPD exacerbations in the previous 12 months (69 mL). Tozorakimab 600 mg showed similar numerical improvements in clinic pre-BD FEVi in former and current smokers (Figure 2).

Changes from baseline in post-BD FEVi at Weeks 12 and 28 are summarised in Table 5 and Figure 3. A trend towards improvement was observed at both Week 12 (LSMean difference 0.067 L [80% CL 0.017, 0.116]) and Week 28 (LSMean difference 0.070 L [80% CL 0.020, 0.120]) in favour of tozorakimab 600 mg compared with placebo. This difference can be seen in the separation of the lines in Figure 3.

Table 5 Change from baseline through Week 28 in post-BD FEVi (L) (as measured in the clinic) treatment comparisons, MMRM (ITT population)*

* Results are based on the MMRM analysis. Fixed factors of the model are log-transformed eosinophil value, background medication strata, geographical region, number of exacerbations during the previous 12 months, visit, study intervention and the baseline*visit and study inlervenlion*visil interactions. Baseline value is considered as covariate. Visit within subject are considered as repeated measurements. An unstructured covariance matrix has been used to describe the correlations between

For the secondary endpoint of change from baseline in pre-BD FVC through Week 28 by extent of emphysema (< 10% and > 10%), for participants with baseline extent of emphysema of > 10%, a clinically significant improvement with tozorakimab 600 mg compared with placebo was observed at Week 28 (LSMean difference 0.191 L [80% CI: 0.047,0.335]) timepoints. No statistically or clinically significant difference was observed for participants with an extent of emphysema of < 10%.

For change from baseline in post-BD FVC through Week 28 by extent of emphysema (< 10% and > 10%), for participants with emphysema of > 10%, a clinically and nominally statistically significant difference in favour of tozorakimab was observed at both the Week 12 (LSMean difference 0.131 L [80% CL 0.018,0.244]) and Week 28 (LSMean difference 0.164 L [80% CL 0.029,0.300]) timepoints. No statistically or clinically significant improvement was observed for participants with an extent of emphysema of < 10%.

Results of the exploratory endpoint of change from baseline in pre-BD FVC through Week 36 are shown in Table 6.

Table 6 Change from baseline through Week 36 in pre-BD FVC (L) (as measured in the clinic) treatment comparisons, MMRM (ITT population)* observations on a subject between visits, and Kenward-Roger correction has been used for degrees of freedom approximation in the generation of model. The significance of the treatment effect has been tested at a 10% one-sided level of significance. Abbreviations: BD Bronchodilator. CI Confidence interval. FVC Forced Vital Capacity. LSMean Least-square mean. MMRM Repeated measures mixed effects analysis of covariance model, n Number of subjects in analysis. SE Standard Error.

There was a consistent numerical trend in favour of the tozorakimab 600 mg group compared with the placebo group. A clear separation of the lines is evident from Week 2 (Figure 4).

Fewer participants experienced a COPDCompEx event in the tozorakimab group (41.8%) compared with placebo (52.9%). There was no statistically significant difference in the tozorakimab group in the time to first CompEx event based on the period from baseline to Week 28 compared with the placebo group (Table 7), however the HR indicated that at any point in time, there was a numerical reduction in risk of CompEx event of 21%. A Kaplan -Meier plot of the time to first COPDCompEx event is shown in Figure 5; there was some separation of the lines throughout the study in favour of the tozorakimab 600 mg group which was clinically meaningful.

Table 7 Time to First COPDCompEx Event (Days) Based on the Period from Baseline to 4 Weeks After Last Dose (Week 28) (ITT Population) Subgroups - Based on Smoking Status and Eosinophil Count

For the subgroup analysis of time to first CompEx event by smoking status, the reduction in risk of CompEx with tozorakimab 600mg compared to placebo for former smokers (hazard ratio 0.72, 80% CI (0.48, 1.07) was numerically greater than in current smokers (Hazard Ratio 0.86, 80% CI (0.47, 1.56) as based on the period from baseline to Week 28 (see Figures 6A and 6B and Table 8).

Table 8 Time to first COPDCompEx event (days) - Cox-regression analysis by subgroup (ITT population)*

For the subgroup analysis of time to first CompEx event by blood eosinophil count (< 150 cell/pL or > 150 cell/pL), the magnitude of reduction in risk of CompEx with tozorakimab 600mg compared to placebo was similar in both subgroups (25% reduction for < 150 cell/pL and 24% reduction for > 150 cell/pLrespectively), based on the period from baseline to Week 28 for either category of eosinophil count (see Table 9).

Table 9 Time to first COPDCompEx event (days) - Cox-regression analysis by subgroup (ITT population) - EOS subgroup*

Efficacy Evaluation Conclusions

Primary Endpoint

• Although no statistically significant difference from placebo was demonstrated for the tozorakimab 600 mg group in change from baseline at Week 12 pre-BD FEVi as measured in the clinic, a numerical improvement of 24 mL was observed. This effect was enhanced in the subgroups of baseline eosinophils > 150 cells/pL (82 mL) and > 2 prior COPD exacerbations in the previous 12 months (69 mL).

Secondary Endpoints

• Numerical improvements in pre-BD FEVi and time-to-first COPDCompex events were observed in current and former smokers

• A trend towards improvement in post-BD FEVi was observed at both Week 12 (LSMean difference 0.067 L [80% CE 0.017, 0.116]) and Week 28 (LSMean difference 0.070 L [80% CE 0.020, 0.120]) in favour of tozorakimab 600 mg compared with placebo

• Extent of emphysema (< 10% and > 10% at baseline) did not appear to have an effect on change from baseline in pre-BD FEVi through Week 28, however for participants with emphysema of > 10%, a clinically significant difference was observed at both the Week 12 and Week 28 timepoints for post- BD FEVi.

• For participants with baseline extent of emphysema of > 10%, a clinically significant trend in improvement was observed from Week 4 through Week 28 in pre-BD FVC which was not replicated for participants with an extent of emphysema of < 10%. However, for participants with emphysema of > 10%, a clinically significant difference was observed at both the Week 12 and Week 28 timepoints for post-BD FVC.

• Fewer participants experienced a COPDCompEx event in the tozorakimab group (41.8%) compared with placebo (52.9%). Although there was no statistically significant difference in the tozorakimab 600 mg group in the time to first CompEx event based on the period from baseline to Week 28 compared with the placebo group, tozorakimab reduced the risk of COPD CompEX COPDCompEx events in the ITT population by 21%. The reduction in risk of CompEx event was more marked in the subgroup of subjects with 2 or more exacerbations in the previous 12 months (39% reduction) and in former smokers (28% reduction).

• Additional analysis undertaken to determine treatment response within different EOS subgroups, demonstrated that subjects with EOS >=150 to <250 showed an improvement in clinic pre BD FEVi compared to placebo from week 2 onwards (Table 10). Improvements in clinic pre BD FEVi was also observed in the EOS >=250 group (Table 10). No numerical improvement in clinic pre-BD FEVi was observed in subjects with <=150 EOS (Table 10).

Table 10 - Change from baseline up to Week 28 in pre-BD FEVi(L) (as measured in clinic) treatment comparisons by different EOS subgroups, MMRM (ITT population) eos <150, >=150 to <250 (not including 250), >=250

Sequences

Further to the sequences listed in Table 1, we provide the following additional sequences:

MEDI3506 VHCDR1 SEQ ID NO 37: SY AMS

MEDI3506 VHCDR2 SEQ ID NO 38: GISAIDQSTYYADSVKG

MEDI3506 VHCDR3 SEQ ID NO 39: QKFMQLWGGGLRYPFGY

MEDI3506 VLCDR1 SEQ ID NO 40: SGEGMGDKYAA MEDI3506 VLCDR2 SEQ ID NO 41: RDTKRPS

MEDI3506 VLCDR3 SEQ ID NO 42: GVIQDNTGV

SEQ ID NO: 43 MEDI3506 heavy chain EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSGISAIDQSTYYA

DSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQKFMQLWGGGLRYPFGYWGQGT

MVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV

LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLG

GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN

STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMT

KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG

NVFSCSVMHEALHNHYTQKSLSLSPGK

SEQ ID NO:44 MEDI3506 light chain

SYVLTQPPSVSVSPGQTASITCSGEGMGDKYAAWYQQKPGQSPVLVIYRDTKRPSGIPERFS

GSNSGNTATLTISGTQAMDEADYYCGVIQDNTGVFGGGTKLTVLGQPKAAPSVTLFPPSSEE

LQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQW

KSHRSYSCQVTHEGSTVEKTVAPTECS

SEQ ID NO:45 IL-33 protein

MKPKMKYSTNKISTAKWKNTASKALCFKLGKSQQKAKEVCPMYFMKLRSGLMIKKEACY

FRRETTKRPSLKTGRKHKRHLVLAACQQQSTVECFAFGISGVQKYTRALHDSSITGISPITEY

LASLSTYNDQSITFALEDESYEIYVEDLKKDEKKDKVLLSYYESQHPSNESGDGVDGKMLM

VTLSPTKDFWLHANNKEHSVELHKCEKPLPDQAFFVLHNMHSNCVSFECKTDPGVFIGVKD

NHLALIKVDSSENLCT ENILFKLSET

Claims

1. A method of treatment of a subject having COPD, the method comprising: administering to said subject an effective amount of an IL-33 signalling axis antagonist, wherein, prior to said administration the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl.

2. A method of improving lung function in a subject having COPD, the method comprising: administering to said subject an effective amount of an IL-33 signalling axis antagonist, wherein, prior to said administration the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl.

3. The method of claim 1 or 2, wherein the subject is a current or former smoker.

4. The method of any one of claims 1-3, wherein the subject is a current smoker.

5. A method of treatment of a subject having COPD, the method comprising: administering to said subject an effective amount of an IL-33 signalling axis antagonist, wherein, prior to said administration the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl, and wherein the subject is a current smoker.

6. A method of improving lung function in a subject having COPD, the method comprising: administering to said subject an effective amount of an IL-33 signalling axis antagonist, wherein, prior to said administration the subject comprises a blood eosinophil count of from <250 to > 150 cells/pl, and wherein the subject is a current smoker.

7. The method according to any one of claims 1-6 wherein prior to said administration the subject comprises a blood eosinophil count of from < 240 to > 150 cells/pl.

8. The method according to any one of claims 1-7 wherein prior to said administration the subject comprises a blood eosinophil count of from < 200 to > 150 cells/pl.

9. The method according to any one of claims 1 or 5, wherein treatment of a subject having COPD results in improving lung function of the subject.

10. The method of any one of claims 1-9, wherein treatment of a subject having COPD, or improving lung function in a subject having COPD, results in reversal of airway obstruction.

11. The method of any one of claims 1-10, wherein the blood eosinophil count is the count immediately prior to said administration of the effective amount of an IL-33 signalling axis antagonist.

12. The method of any one of claims 1-6, 9-11, wherein the subject is selected from a group of subjects comprising a blood eosinophil count of from < 250 to > 150 cells/pl prior to said administration.

13. The method of claim 12, wherein the subject is selected from a group of subjects comprising a blood eosinophil count of from < 240 to > 150 cells/pl prior to said administration.

14. The method of claims 12 or 13, wherein the subject is selected from a group of subjects comprising a blood eosinophil count of from < 200 to > 150 cells/pl prior to said administration.

15. The method of any one of claims 1-6, 9-11, wherein the method further comprises a step of selecting a subject having a blood eosinophil count of from <250 to > 150 cells/pl prior to said administration.

16. The method of claim 15 wherein the method further comprises a step of selecting a subject having a blood eosinophil count of from <240 to > 150 cells/pl prior to said administration.

17. The method of claims 15 or 16, wherein the method further comprises a step of selecting a subject having a blood eosinophil count of from <200 to > 150 cells/pl prior to said administration.

18. The method of any one of claims 1-17, wherein treatment of a subject having COPD, or the improvement of lung function in a subject having COPD, results in increasing pre-bronchodilator (BD) FEVi of the subject by at least 50 ml.

19. The method of any one of claims 1-18, wherein treatment of a subject having COPD, or the improvement of lung function in a subject having COPD, results in increasing pre-bronchodilator (BD) FEVi of the subject by at least 60 ml.

20. The method of any one of claims 1-19, wherein the treatment of a subject having COPD, or the improvement of lung function in a subject having COPD, results in increasing pre-BD-FEVi of the subject by at least 80 ml.

21. The method of any one of claims 1-19, wherein the treatment of a subject having COPD, or the improvement of lung function in a subject having COPD, results in increasing pre-BD-FEVi of the subject by about 80 ml.

22. The method of any one of claims 1-21, wherein the treatment of a subject having COPD, or the improvement of lung function in a subject having COPD, results in increasing post-bronchodilator (BD)-FEVi of the subject by at least 60 ml.

23. The method of any one of claims 18-22, wherein the increase in pre-BD-FEVi or post-BD-FEVi of the subject is achieved by week 12 after administration of the effective amount of the IL-33 signalling axis antagonist.

24. The method of any one of claims 18-22, wherein the increase in pre-BD-FEVi or post-BD-FEVi of the subject is achieved by week 28 after administration of the effective amount of the IL-33 signalling axis antagonist.

25. The method of any one of claims 1-24, wherein the treatment of a subject having COPD, or the improvement of lung function of the subject having COPD, results in increasing pre-bronchodilator (BD) forced vital capacity (FVC) of the subject by at least 60 ml.

26. The method of any one of claims 1-24, wherein the treatment of a subject having COPD, or the improvement of lung function of the subject having COPD, results in increasing pre-BD-FVC of the subject by at least 70 ml.

27. The method of any one of claims 1-24, wherein the treatment of a subject having COPD, or the improvement of lung function of the subject having COPD, results in increasing pre-BD-FVC of the subject by about 70 ml.

28. The method according to any one of claims 1-27, wherein the treatment of a subject having COPD, or the improvement of lung function of the subject having COPD, results in increasing postbronchodilator (BD)-FVC of the subject by at least 60 ml.

29. The method of any one of claims 1-27, wherein the treatment of a subject having COPD, or the improvement of lung function of the subject having COPD, results in increasing post-bronchodilator (BD)-FVC of the subject by about 60 ml.

30. The method of any one of claims 25-29, wherein the increase in pre-BD-FVC or post-BD-FVC of the subject is achieved by week 12 after administration of the effective amount of the IL-33 signalling axis antagonist.

31. The method of any one of claims 25-29, wherein the increase in pre-BD-FVC or post-BD- FVC of the subject is achieved by week 28 after administration of the effective amount of the IL-33 signalling axis antagonist.

32. The method of any one of claims 1-31, wherein the treatment of a subject having COPD, or the improvement of lung function in a subject having COPD, results in increasing the time-to-first CompEx event in said subject.

33. The method of claim 32, wherein the time-to-first CompEx event in the subject is increased by about 4 weeks, or by about 5 weeks, or by about 6 weeks relative to a control subject having COPD who has not received the IL-33 signalling axis antagonist.

34. The method of any one of claims 1-33, wherein the treatment of a subject having COPD, or the improvement of lung function in a subject having COPD, results in reducing the rate of CompEx events in the subject having COPD.

35. The method of claim 34, wherein the rate of CompEx events is reduced by at least 20%, by at least 25%, by at least 27%, after administration of an effective amount of the IL-33 signalling axis antagonist compared to a control subject having COPD who has not received the IL-33 signalling axis antagonist.

36. The method of claim 34 or 35, wherein the rate of CompEx events is reduced over a 28 week period.

37. The method of any one of claims 1-36, wherein the subject has chronic bronchitis.

38. A method of increasing the time-to-first CompEx event in a subject having COPD, the method comprising: administering to said subject an effective amount of an IL-33 signalling axis antagonist, wherein the subject is a current smoker.

39. A method of reducing the rate of CompEx events in a subject having COPD, the method comprising: administering to said subject an effective amount of an IL-33 signalling axis antagonist, wherein the subject is a current smoker.

40. The method of claim 39, wherein the time-to-first CompEx event in the subject is increased by about 4 weeks, or by about 5 weeks, or by about 6 weeks relative to a control subject having COPD who has not received the IL-33 signalling axis antagonist.

41. The method of claims 39, or 40, wherein the rate of CompEx events is reduced by at least 20%, or by at least 25%, or by at least 27% after administration of an effective amount of the IL-33 signalling axis antagonist compared to a control subject who has not received the IL-33 signalling axis antagonist.

42. The method of any one of claims 39 to 41, wherein the rate of CompEx events is reduced over a 28 week period.

43. The method of any one of claims 38-42, wherein, prior to said administration the subject comprises a blood eosinophil count of greater than or equal to (>) 150 cells/pl.

44. The method of any one of claims 38-42, wherein, prior to said administration the subject comprises a blood eosinophil count of from < 250 to > 150 cells/pl.

45. The method of any one of any one of claims 38-44, wherein prior to said administration the subject comprises a blood eosinophil count of from < 240 to > 150 cells/pl.

46. The method of any one of claims 38-45, wherein, prior to said administration the subject comprises a blood EoS count of from < 200 to > 150 cells/pl.

47. The method of any one of claims 38-46, wherein the blood eosinophil count is the count immediately prior to said administration.

48. The method of any one of claims 38-47, wherein the subject is selected from a group of subjects comprising said blood eosinophil count prior to said administration.

49. The method of any one of claims 38-48, wherein the method further comprises a step of selecting a subject having said blood eosinophil count prior to said administration.

50. A method of selecting a subject having COPD for treatment with an effective amount of IL-33 signalling axis antagonist, the method comprising: measuring the blood eosinophil count of the subject; selecting said subject for said treatment if the blood eosinophil count of the subject is from < 250 to > 150 cells/pl.

51. A method of selecting a subject according to claim 50 wherein said method further comprises administering an effective amount of an IL-33 signalling axis antagonist to the subject.

52. A method of selecting a subject according to claim 50 or 51, wherein said subject is a current smoker.

53. The method of any one of claims 1-52, wherein the subject comprises a BCSS score of around 7 or higher, 7.1 or higher, 7.2 or higher, 7.3 or higher, 7.4 or higher, 7.429 or higher.

54. The method of any one of claims 1-53, wherein the subject comprises a SGRQ score of around 58 or higher, 58.1 or higher, 58.2 or higher, 58.239 or higher.

55. The method of any one of claims 1-54, wherein the subject comprises an extent of emphysema of <10%.

56. The method of any one of claims 1-55, wherein the subject has had 2 or more AECOPD in the 12 months prior to treatment.

57. The method of any one of claims 1-55, wherein the subject has had 2 or more moderate AECOPD and/or one or more severe AECOPD in the 12 months prior to treatment.

58. The method of any one of claims 18-31, wherein increasing pre-bronchodilator (BD) FEVi of the subject, increasing post- bronchodilator (BD)-FEVi, increasing pre-bronchodilator (BD) forced vital capacity (FVC), increasing post-bronchodilator (BD)-FVC, is relative to a baseline level.

59. The method of any one of claims 53, 54, or 55, wherein the BCSS score, the SGRQ score, and the extent of emphysema are measured at baseline.

60. The method of claims 58 or 59, wherein the baseline is the level in a subject prior to said administration.

61. The method of any preceding claim, wherein the IL-33 signalling axis antagonist is an antibody, an antigen binding fragment, or a variant thereof.

62. The method of claim 61, wherein the antibody is an anti -IL-33 antibody, anti-ST2 antibody, anti- ILl-RacP antibody, an antigen binding fragment, or a variant thereof.

63. The method of claims 61 or 62, wherein the antibody is an anti -IL-33 antibody, an antigen binding fragment, or variant thereof.

64. The method of claim 63, wherein the anti -IL-33 antibody, antigen binding fragment, or variant thereof comprises a VH domain comprising a VHCDR1 having the sequence set forth in SEQ ID NO:37, a VHCDR2 having the sequence set forth in SEQ ID NO:38, a VHCDR3 having the sequence set forth in SEQ ID NO:39, and a VL domain comprising a VLCDR1 having the sequence set forth in SEQ ID NO:40, a VLCDR2 having the sequence set forth in SEQ ID NO:41, and a VLCDR3 having the sequence set forth in SEQ ID NO:42.

65. The method of claim 63, or 64, wherein the anti-IL-33 antibody, an antigen binding fragment, or variant thereof comprises a VH domain having the sequence set forth in SEQ ID NO: 1 or a sequence 80, 85, 90 or 95% identical thereto, and a VL domain having the sequence set forth in SEQ ID NO: 19 or a sequence 80, 85, 90 or 95% identical thereto.

66. The method of claims 63, 64, or 65, wherein the anti-IL-33 antibody, an antigen binding fragment, or variant thereof comprises a VH domain having the sequence set forth in SEQ ID NO: 1, and a VL domain having the sequence set forth in SEQ ID NO: 19.

67. The method of any of claims 61-66, which is an antibody.

68. The method of claim 67, wherein the antibody is a monoclonal antibody.

69. The method of claim 68 wherein the monoclonal antibody is an IgGl.

70. The method of any one of claims 67-69, wherein the anti -IL-33 antibody comprises a heavy chain having the sequence set forth in SEQ ID NO:43 or a sequence 80, 85, 90 or 95% identical thereto and a light chain having the sequence set forth in SEQ ID NO:44 or a sequence 80, 85, 90 or 95% identical thereto.

71. The method of claim 70, wherein the anti-IL-33 antibody comprises a heavy chain having the sequence set forth in SEQ ID NO:43 and a light chain having the sequence set forth in SEQ ID NO:44.

72. The method of any one of claims 61-71, wherein the antibody is tozorakimab.

73. The method of claims 1 to 72, wherein the effective amount of the IL-33 signalling axis antagonist is comprised in a pharmaceutical composition, comprising one or more excipients.

74. The method of claims 1 to 73, wherein the effective amount of the IL-33 signalling axis antagonist is a dose of between 300mg to 600mg.

75. The method of claims 1 to 74, wherein the IL-33 signalling axis antagonist or a pharmaceutical composition thereof is administered to the subject every 2 weeks (Q2W), 4 weeks (Q4W), five weeks (Q5W), 6 weeks (Q6W), seven weeks (Q7W), or 8 weeks (Q8W).

76. The method of any preceding claim, wherein the IL-33 signalling axis antagonist or a pharmaceutical composition thereof is administered to the subject at a dose of 600 mg every 4 weeks (Q4W).

77. The method of any preceding claim, wherein the IL-33 signalling axis antagonist or a pharmaceutical composition thereof is administered to the subject at a dose of 300 mg every 2 weeks (Q2W).

78. The method of any preceding claim, wherein the IL-33 signalling axis antagonist or a pharmaceutical composition thereof is administered to the subject at a dose of 300 mg every 4 weeks (Q4W).

79. The method of any preceding claim, wherein the IL-33 signalling axis antagonist or a pharmaceutical composition thereof is administered to the subject at a dose of 300 mg every 8 weeks (Q8W).

80. The method of any preceding claim, the IL-33 signalling axis antagonist or a pharmaceutical composition thereof is administered to the subject subcutaneously.

81. The method of any preceding claim, the IL-33 signalling axis antagonist or a pharmaceutical composition thereof is administered to the subject by injection.